2-biphenyl-carbapenem antibacterial agents

ABSTRACT

Carbapenems of the formula ##STR1## are useful antibacterial agents.

BACKGROUND OF THE INVENTION

The present invention relates to antibacterial agents of the carbapenemclass, in which the 2-position sidechain is characterized by a biphenylmoiety, substituted by various substituents, as described in more detailfurther below.

Thienamycin was an early carbapenem antibacterial agent having a broadspectrum; it has the following formula: ##STR2## Later, N-formimidoylthienamycin was discovered; it has the formula: ##STR3##

The 2-biphenyl-carbapenems of the present invention are notcharacterized by a broad antibacterial spectrum such as that ofthienamycin or N-formimidoyl thienamycin. Rather, their spectrum ofactivity is largely limited to gram positive microorganisms, especiallymethicillin resistant Staphylococcus aureus (MRSA), methicillinresistant Staphylococcus epidermidis (MRSE), and methicillin resistantcoagulase negative Staphylococi (MRCNS). The antibacterial compounds ofthe present invention thus comprise an important contribution to therapyof these difficult to control pathogens. Moreover, there is anincreasing need for agents effective against such pathogens (MRSA/MRCNS)which are at the same time safe, i.e., free from undesirable toxic sideeffects. No β-lactam antibacterial has yet been found which meets theserequirements. And, the current agent of choice, vancomycin, aglycopeptide antibacterial, is experiencing an ever increasing amount ofresistance in the MRSA/MRCNS pathogens.

More recently, carbapenem antibacterial agents have been described whichhave a 2-substituent which is an aryl moiety optionally substituted by,e.g., aminomethyl and substituted aminomethyl. These agents aredescribed in U.S. Pat. Nos. 4,543,257 and 4,260,627 and have theformula: ##STR4##

However, there is no description or suggestion of a biphenyl2-substituent such as characterizes the compounds of the presentinvention, nor is there any suggestion of the suprisingly betteranti-MRSA/MRCNS activity of the compounds of the present invention.

EP-A-0277 743 describes a particular class of compounds of the formula:##STR5## but this limited teaching in no way suggests the totallydifferent compounds of the present invention, nor their surprisinglybetter anti-MRSA/MRCNS activity.

SUMMARY OF INVENTION

The present invention provides novel carbapenem compounds of theformula: ##STR6## wherein: R is H or CH₃ ;

R¹ and R² are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂--, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂ CHCH(OH)--, F₃CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;

R^(a) are independently selected from the group consisting of hydrogenand the radicals set out below:

(a) a trifluoromethyl group: --CF₃ ;

(b) a halogen atom: --Br, --Cl, --F, or --I;

(c) C₁ -C₄ alkoxy radical: --OC₁₋₄ alkyl, wherein the alkyl isoptionally mono-substituted by R^(q), where

R^(q) is a member selected from the group consisting of --OH, --OCH₃,--CN, --C(O)NH₂, --OC(O)NH₂, CHO --OC(O)N(CH₃)₂, --SO₂ NH₂, --SO₂N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F, --CF₃, --COOM^(a) (where M^(a) ishydrogen, alkali metal, methyl or phenyl), tetrazolyl (where the pointof attachment is the carbon atom of the tetrazole ring and one of thenitrogen atoms is mono-substituted by M^(a) as defined above) and --SO₃M^(b) (where M^(b) is hydrogen or an alkali metal);

(d) a hydroxy group: --OH;

(e) a carbonyloxy radical: --O(C═O)R^(s), where

R^(s) is C₁₋₄ alkyl or phenyl, each of which is optionallymono-substituted by R^(q) as defined above;

(f) a carbamoyloxy radical: --O(C═O)N(R^(Y))R^(z) where

R^(Y) and R^(z) are independently H, C₁₋₄ alkyl (optionallymono-substituted by R^(q) as defined above), together a 3- to 5-memberedalkylidene radical to form a ring (optionally substituted with R^(q) asdefined above) or together a 2- to 4-membered alkylidene radical,interrupted by --O--, --S--, --S(O)-- or --S(O)₂ --, to form a ring(where the ring is optionally mono-substituted with Rq as definedabove);

(g) a sulfur radical: --S(O)_(n) --R^(S) where n=0-2, and R^(s) isdefined above;

(h) a sulfamoyl group: --SO₂ N(R^(Y))R^(z) where R^(Y) and R^(z) are asdefined above;

(i) azido: N₃

(j) a formamido group: --N(R^(t))(C═O)H, where

R^(t) is is H or C₁₋₄ alkyl, and the alkyl thereof is optionallymono-substituted by R^(q) as defined above;

(k) a (C₁ -C₄ alkyl)carbonylamino radical: --N(R^(t))(C═O)C₁₋₄ alkyl,where R^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above;

(l) a (C₁ -C₄ alkoxy) carbonylamino radical: --N(R^(t))(C═O)OC₁₋₄ alkyl,where R^(t) is as defined above, and the alkyl group is also optionallymono-substitued by R^(q) as defined above;

(m) a ureido group: --N(R^(t))(C═O)N(R^(y))R^(z) where R^(t), R^(y) andR^(z) are as defined above;

(n) a sulfonamido group: --N(R^(t))SO₂ R^(s), where R^(s) and R^(t) areas defined above;

(o) a cyano group: --CN;

(p) a formyl or acetalized formyl radical: --(C═O)H or --CH(OCH₃)₂ ;

(q) (C₁ -C₄ alkyl)carbonyl radical wherein the carbonyl is acetalized:--C(OCH₃)₂ C₁₋₄ alkyl, where the alkyl is optionally mono-substituted byR^(q) as defined above;

(r) carbonyl radical: --(C═O)R^(s), where R^(s) is as defined above;

(s) a hydroximinomethyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group: --(C═NOR^(z))R^(y) whereR^(y) and R^(z) are as defined above, except they may not be joinedtogether to form a ring;

(t) a (C₁ -C₄ alkoxy)carbonyl radical: --(C═O)OC₁₋₄ alkyl, where thealkyl is optionally mono-substituted by R^(q) as defined above;

(u) a carbamoyl radical: --(C═O)N(R^(y))R^(z) where R^(y) and R^(z) areas defined above;

(v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical in whichthe nitrogen atom may be additionally substituted by a C₁ -C₄ alkylgroup: --(C═O)--N(OR^(y))R^(z) where R^(y) and R^(z) are as definedabove, except they may not be joined together to form a ring;

(w) a thiocarbamoyl group: --(C═S)N(R^(y))(R^(z)) where R^(y) and R^(z)are as defined above;

(x) carboxyl: --COOM^(b), where M^(b) is as defined above;

(y) thiocyanate: --SCN;

(z) trifluoromethylthio: --SCF₃ ;

(aa) tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above;

(ab) an anionic function selected from the group consisting of:phosphono [P═O(OM^(b))₂ ]; alkylphosphono {P═O(OM^(b))--[O(C₁ -C₄alkyl)]}; alkylphosphinyl [P═O(OM^(b))--(C₁ -C₄ alkyl)]; phosphoramido[P═O(OM^(b))N(R^(y))R^(z) and P═O(OM^(b))NHR^(x) ]; sulfino (SO₂ M^(b));sulfo (SO₃ M^(b)); acylsulfonamides selected from the structuresCONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂ NM^(b)CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where

R^(X) is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatichydrocarbon group having 5 or 6 ring atoms, in which a carbon atom isthe point of attachment, in which one of the carbon atoms has beenreplaced by a nitrogen atom, in which one additional carbon atom isoptionally replaced by a heteroatom selected from O or S, and in whichfrom 1 to 2 additional carbon atoms are optionally replaced by anitrogen heteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), as defined above; M^(b) is as defined above;and R^(y) and R^(z) are as defined above;

(ac) C₅ -C₇ cycloalkyl group in which one of the carbon atoms in thering is replaced by a heteroatom selected from O, S, NH or N(C₁ -C₄alkyl) and in which one additional carbon atom may be replaced by NH orN(C₁ -C₄ alkyl), and in which at least one carbon atom adjacent to eachnitrogen heteroatom has both of its attached hydrogen atoms replaced byone oxygen thus forming a carbonyl moiety and there are one or twocarbonyl moieties present in the ring;

(ad) C₂ -C₄ alkenyl radical, optionally monosubstituted by one of thesubstituents (a) to (ac) above and phenyl which is optionallysubstituted by R^(q) as defined above;

(ae) C₂ -C₄ alkynyl radical, optionally monosubstituted by one of thesubstituents (a) to (ac) above;

(af) C₁ -C₄ alkyl radical;

(ag) C₁ -C₄ alkyl mono-substituted by one of the substituents (a)-(ac)above;

(ah) a 2-oxazolidinonyl moiety in which the point of attachment is thenitrogen atom of the oxazolidinone ring, the ring oxygen atom isoptionally replaced by a heteroatom selected from --S-- and >NR^(t)(where R^(t) is as defined above) and one of the saturated carbon atomsof the oxazolidinone ring is optionally mono-substituted by one of thesubstituents (a) to (ag) above;

M is selected from:

(i) hydrogen;

(ii) a pharmaceutically acceptable esterifying group or removablecarboxyl protecting group; or

(iii) an alkali metal or other pharmaceutically acceptable cation.

DETAILED DESCRIPTION OF THE INVENTION

The manufacture of compounds of Formula I may be carried out in athree-stage synthesis scheme followed by a final step that allows forthe removal of any protecting groups. The objective of the firstsynthetic stage is to produce a base biphenyl compound which may beconverted to the two-position substituent of the carbapenem of FormulaI. The objective of the second synthetic stage is to attach the basebiphenyl to the carbapenem. Finally, the objective of the thirdsynthetic stage is to substitute the biphenyl with the desired R^(a).This third synthetic stage may either be performed after the firstsynthetic stage or during or after the second synthetic stage accordingto the nature of the various R^(a).

Flow Sheets AA through AF demonstrate suggested first stage syntheses.Flow Sheets B and C demonstrate two alternative second stage syntheses.The third synthesis varies according to the selected R^(a).

The suggested first synthesis herein, Flow Sheets AA through AF, showpreparation of various 3-bromo biphenyls each designated as B1 for usein either Flow Sheet B or C. In one instance, an aryl stannane C3 isproduced for use in Flow Sheet C. Following is a general description ofthe chemistry employed in each procedure.

AA: Synthesis of 3-bromo-5-substituted-biphenyls

A 3-bromo-5-substituted biphenyl intermediate is obtained by startingwith a commerically available p-aminobiphenyl. The amino group serves todirect substitution to the two ortho positions (3 and 5), after which itcan be removed reductively. However, in order to provide 5-substitutedbiphenyl compounds, the p-aminobiphenyl starting material AA1 asdepicted in Flow Sheet AA is first protected by acetylation and thennitrated with nitrous acid before bromination is carried out.

Nitration is carried out with fuming nitric acid in the presence ofacetic acid and acetic anhydride, after which deprotection isaccomplished with sodium hydroxide using ethanol as a solvent andapplying heat. These procedures are well known and are described in moredetail, for example, in Dell 'Erba et al., Tetrahedron, 27, 113 (1971).

Bromination is carried out in dioxane and water while the reactionmixture is maintained at near 0° C. with an ice-water bath. Aqueous 5Nsodium hydroxide is added followed by bromine to produce compound AA2.

The original p-amino group is next removed by diazotization with sodiumnitrite and concentrated sulfuric acid followed by reduction withpowdered copper at ambient temperature to produce compound AA3.

The 5-nitro substituent is next converted to 5-amino group with stannouschloride dihydrate and this product then becomes the basis for obtaininga number of R^(a) substituents on the meta-biphenyl moiety whichcharacterize the compounds of the present invention. For example, the5-fluoro compound can be obtained by thermal decomposition of thecorresponding diazonium hexafluorophosphate salt, or the latter can betreated with potassium ethylxanthate to give the 5-ethylxanthylbiphenylcompound. This intermediate can then be the basis for obtaining the5-methylthiobiphenyl compound of the present invention, or otherunsubstituted and substituted alkyl mercaptans such as the5-(2'-t-butyldimethylsilyloxyethylthio)biphenyl compound.

Returning to the diazotized 5-amino compound as a starting point forfurther synthesis, hydroxylation provides the 5-hydroxybiphenyl compoundof the present invention, which can then be alkylated by treatment withsodium hydride followed by addition of an alkyl halide such as methyliodide, to give the 5-alkoxy, e.g., 5-methoxybiphenyl compound of thepresent invention. The 5-hydroxy compound can also be protected bytreatment with t-butyldimethysilyl chloride, creating an intermediatefor synthesis of the desired hydroxybiphenyls of the present invention.The latter synthons, as the corresponding Grignard reagent or arylstannane, allow for a meta-biphenyl moiety when attached to thecarbapenem nucleus. ##STR7##

AB: Synthesis of 3-bromo-4',5-disubstituted biphenyls

The 3-bromo-5-substituted biphenyls prepared in accordance with FlowSheet AA above and also a simple 3-bromo biphenyl can be the startingpoint for introduction of a 4'-substituent in accordance with thefollowing procedures. For example, the 4'-acetyl of the 3-bromo-5-fluorocompound can be made using the procedure of Berliner and Blommers, JACS,73, 2479 (1951), after which, treatment with m-chloroperoxybenzoic acidin refluxing 1,2-dichloroethane gives the 3-bromo-4'-acetoxy-5-fluorocompound. Both of these compounds are compounds of the presentinvention.

The 4'-acetoxy compound can be converted to the 4'-hydroxy compound bytreatment with sodium methoxide, and then protected usingt-butyldimethylsilyl chloride in accordance with procedures describedabove, said protected compound being useful in further synthesis.

The 4'-acetyl compound can also be the starting point for conversion toother 3-bromo-5-fluoro-4'-substituted biphenyl compounds of the presentinvention. For example, oxidation with sodium hypobromite, provides the4'-carboxyl group, which can then be converted by borane reduction tothe corresponding alcohol, both compounds of the present invention. The4'-hydroxymethyl compound can then be protected witht-butyldimethylsilyl chloride as described above, for use as anintermediate in synthesis of other 3-bromo-5-fluoro-4'-substitutedbiphenyls.

The 4'-acetyl compound can also be converted to an amino group by aBeckmann rearrangement process and hydrolysis, which in turn can bediazotized to provide diazonium salts capable of producing other4'-substituents in the same fashion as described above. ##STR8##

AC: Synthesis of 3-bromo-4',5',5-substituted-biphenyls

Starting with the 3-bromo-4'-amino intermediate prepared as described inconnection with Flow Sheet AB above, it is possible to prepare compoundsof the present invention in which the 5'-position is substituted. Once a4'-N-acetamido group is in place, it can be used to direct substitutionof a nitro group which can be converted to various substituents, formingcompounds of the present invention, in the same manner as was describedabove under Flow Sheet AA. ##STR9##

AD: Synthesis of 3-stannyl-3',4',5',5-substituted biphenyl

Starting with 3-bromo-4'-acetamido-5'-nitro intermediate, AC1, describedabove, it is possible to prepare biphenyl having 3', 4', 5' and 5position substitution. Referring to Flow Sheet AD, intermediate AC1 isstannylated in a reaction with hexamethylditin in an aromatichydrocarbon solvent, such as toluene or xylene, at elevated temperaturesusing tetrakistriphenylphosphinepalladium as a catalyst to produceintermediate AD1. Subsequently, the aryl stannane AD1 may be brominatedin dioxane water at ambient temperatures or below to produce an arylstannane AD2 with 3', 4', 5' and optional 5 position substitution. Eachof these substituents, through subsequent art recognized procedures, maybe replaced as desired to produce the aryl stannane C3, which may beemployed in further synthesis of the carbapenems herein as according toFlow Sheet C below. Optionally, aryl stannane C3 may be converted to aGrignard Reagent analogous to B1. ##STR10##

AE: Synthesis of 3-bromo-3', 4', 5'-substituted-biphenyls

Starting with readily available starting materials, 1,3-dibromobenzeneand the appropriately substituted iodobenzene, it is possible to preparebiphenyls having 3', 4' and 5' position substitution. Referring to FlowSheet AE 1,3-dibromobenzene AE1 is converted to boronic acid AE2 byfirst reacting with butyl lithium in anhydrous THF or ether at about-78° C. followed by addition of triisopropyl borate. The resultantintermediate is worked up with sodium hydroxide and acidified. Boronicacid AE2 is subsequently reacted with the appropriate iodobenzene AE3 intoluene and aqueous sodium carbonate withtetrakistriphenylphosphinepalladium as a catalyst to produce the 3-bromobiphenyl B1. This reaction to B1 is well known in art with referencemade herein to N. Miyaura, T. Yanagi and A. Suzuki, Syn. Comm., 11, 513(1981). ##STR11##

AF: Synthesis of 3-bromo-3',4',5'-substituted-biphenyls

Alternatively, starting with readily available starting materials,difluorosilylbenzenes and, as above, iodobenzenes, it is possible toprepare biphenyls having 3', 4' and 5' position substitution. Referringto Flow Sheet AF, meta-bromoethyldifluorosilylbenzene AF1 is reacted inDMF with iodobenzene derivative AF2 and a desilylating agent, KF, usingdiallylpalladium chloride catalyst at elevated temperature to produce3-bromo biphenyl B1. This reaction is known in the art with referencemade herein to Y. Hatanaka, S. Fukushima and T. Hiyama, Chem. Lett.,1711 (1989). ##STR12##

All of the above synthetic schemes relate to preparation of biphenylcompounds substituted at various positions to be used in the formationof Grignard reagents or aryl stannanes, which, in turn, as shown below,are used to couple the already substituted biphenyl compounds to thecarbapenem nucleus just prior to its formation (ring closure), or with asuitably activated intact carbapenem synthon. However, it is immediatelyclear to those skilled in the art that certain R^(a) listed above, ifsubstituted on B1 or C3 may not be compatible with the second stagesynthesis. Thus, it is also possible, as an alternative synthetic schemefor preparation of the compounds of the present invention, to generatethe desired substituents at the appropriate positions on the biphenylnucleus after the biphenyl nucleus itself has already been attached tothe carbapenem nucleus. More precisely, however, this is a process ofmodifying compatible precursor substituents already in place on thebiphenyl nucleus so as to convert them to additional desiredsubstituents.

The identity of the precursor substituent where employed on B1 or C3 isnot crucial and the precursor substituent may itself be a protected orunprotected R^(a). Preferably the precursor substituent is compatible tothe synthesis to B1 or C3. An incompatible precursor substituent wouldobviously require additional synthesis to make. Critically it isrequired that the precursor substituent is compatible with the chemistrydepicted in Flow Sheets B and C and may be converted to more desirablesubstitution. Preferred precursor substituents are methyl, hydroxymethyland protected hydroxymethyl for Flow Sheet B.

Thus, as to the R^(a) substituent on compound B1 or C3, it may be anR^(a) with or without protecting groups, preferably it is stable to theconditions of producing compound B1 or C3 and it must be stable to theconditions of subsequently adding B1 or C3 to the carbapenem.Alternatively, it may be a precursor substituent which is optionallystable to the conditions of making B1 or C3, which is stable to theconditions of adding B1 or C3 to the carbapenem and which is convertibleto a desired R^(a) or to another precursor substituent.

As stated above, the second stage synthesis is to attach the basebiphenyl to the 2-position of the carbapenem. With stable R^(a) orsuitable precursor substituents therefore, biphenyl B1 may be added toazetidin-2-one B2 in a Grignard reaction as shown in Flow Sheet B. TheGrignard reaction requires that B1 be converted to a Grignard reagent byreaction with magnesium and 1,2-dibromoethane in THF from 20° C. to 60°C. and subsequently contacting B1 as a Grignard reagent with B2 in THFat from -70° C. to about 20° C. to produce azetidin-2-one B3.Alternatively, B1 may be reacted with t-butyllithium, n-butyllithium, orthe like in THF at from -78° to -50° C. followed by the addition ofmagnesium bromide to produce the same Grignard reagent. R^(i) of B3 isin practice pyrid-2-yl but may clearly be a variety of substituentsincluding aromatic and heteroaromatic substituents. Further R^(i) mightbe for example phenyl, 2-pyrimidinyl or 2-thiazolyl.

Azetidin-2-one B3 is an intermediate that may be ring closed to acarbapenem. It is on this intermediate that R^(a) or precursorsubstituent such as (t-butyldimethylsilyloxy)methyl may be modifiedwhere such modification is incompatible with the carbapenem nucleus. Forexample, a convenient reaction to remove a t-butyldimethylsilyl group ofB3 is to expose it to 2% dilute solution of sulfuric acid in methanol at0° C. for from a few minutes to several hours. If thet-butyldimethylsilyl group was removed from carbapenem B4 under the sameconditions after cyclization of B3 to a carbapenem, a substantialportion of the carbapenem would be degraded and lost. Thus, modificationof the precursor substituent in this instance and replacement withanother precursor substituent or even R^(a) is best performed beforeclosing the carbapenem. Of course it is possible to remove thet-butyldimethylsilyl group in reduced yield after cyclization of B3 to acarbapenem by reaction with tetra-n-butylammonium fluoride and aceticacid in THF.

Compound B3 may be ring closed to carbapenem B4 by refluxing in xylenewith a trace of p-hydroquinone for about 1 to 2 hours in an inertatmosphere. It is on this intermediate that final elaboration of R^(a)from a precursor substituent, e.g. hydroxymethyl, may be accomplished.Removal of the carboxyl and hydroxyl protecting groups then provides thefinal compound Formula I. Such final elaboration and deprotection isdescribed in further detail below. ##STR13##

Flow Sheet C shows an alternative second stage synthesis, i.e.attachment of the base biphenyl such as B1 to the 2-position of thecarbapenem. This synthesis involves a palladium catalyzed cross-couplingreaction between a carbapenem triflate and a suitably substitutedarylstannane, a process which is described in U.S. pat. appl. Ser. No.485,096 filed Feb. 26, 1990, hereby incorporated by reference. In orderto apply this synthesis, it is first necessary to modify bromobiphenylB1 to the trimethylstannylbiphenyl C3. This is accomplished by reactingB1 with t-butyllithium in THF at from -78° to -50° C. followed by theaddition of trimethyltin chloride. Alternatively, C3 may be prepared bysimply heating B1 with hexamethylditin in the presence oftetrakistriphenylphosphine palladium in toluene solution. At thisintermediate, it may be desireable to remove certain protecting groupsif employed on a precursor substituent R^(a). For instance, a protectinggroup such as t-butyldimethylsilyl on a hydroxymethyl substituent may beremoved by exposure to tetra-n-butylammonium fluoride in THF yielding aparticular C3. If the t-butyldimethylsilyl group was removed fromcarbapenem C4 under the same conditions, a substantial portion of thecarbapenem would be degraded and lost. Thus modification of theprecursor substituent in this instance and replacement with anotherprecursor substituent or even R^(a) is best performed before attachmentto the carbapenem. Referring again to Flow Sheet C, the 2-oxocarbapenamC1 is reacted with a suitable trifluoromethanesulfonyl source, such astrifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chlorideand the like, in the presence of an organic nitrogen base, such astriethylamine, diisopropylamine and the like, in polar aprotic solvent,such as tetrahydrofuran or methylene chloride. An organic nitrogen base,such as triethylamine and the like, is then added to the reactionsolution followed immediately by a silylating agent, such astrimethylsilyl trifluoromethanesulfonate to provide intermediate C2. Anaprotic polar coordinating solvent, such as DMF,1-methyl-2-pyrrolidinone and the like, is added. This is followed by theaddition of a palladium compound, such astris(dibenzylideneacetone)dipalladium-chloroform, palladium acetate andthe like, a suitably substituted phenylphosphine, such astris(4-methoxyphenyl)phosphine, tris(2,4,6-trimethoxyphenyl)phosphineand the like, and the stannane C3. A metal halide, such as lithiumchloride, zinc chloride and the like, is added and the reaction solutionis allowed to warm and is stirred at a suitable temperature, such as 0°to 50° C., for from a few minutes to 48 hours. The carbapenem C4 isobtained by conventional isolation/purification methodology known in theart.

Generally speaking, the milder conditions of the synthesis shown in FlowSheet C allow for a wider range of functional groups R^(a) to be presentthan the synthesis illustrated in Flow Sheet B. However, in certaincases, it is advantageous fo the R^(a) substituent(s) of the stannane C3to be introduced in a protected or precursory form. ##STR14## Finalelaboration of R^(a) from a precursor substituent, e.g. hydroxymethyl,may be accomplished on carbapenem intermediate C4. Removal of hydroxyland ester protecting groups then provides the final compound of FormulaI. Such final elaboration and deprotection is described in furtherdetail below.

Azetidin-2-one B2, a pyridyl-thioester, is a well known compound in theproduction of carbapenems. Diverse synthetic schemes useful to make B2may be imagined by the skilled artisan. Particularly useful to theinstant invention is a synthetic scheme set out further in Flow Sheet Dbelow in which the symbol R is as defined above. The steps for preparingintermediate B2 are analogous to the procedures described, for example,in U.S. Pat. Nos. 4,260,627 and 4,543,257; L. D. Cama et al.Tetrahedron, 39, 2531 (1983); R. N. Guthikonda et al. J. Med. Chem., 30,871 (1987) hereby incorporated by reference. ##STR15##

The steps for preparing the 2-oxocarbapenam intermediate C1 are wellknown in the art and are explained in ample detail by D. G. Melillo etal., Tetrahedron Letters, 21, 2783 (1980), T. Salzmann et al., J. Am.Chem. Soc., 102, 6161 (1980), and L. M. Fuentes, I. Shinkai, and T. N.Salzmann, J. Am. Chem. Soc., 108, 4675 (1986). The syntheses are alsodisclosed in U.S. Pat. No. 4,269,772, U.S. Pat. No. 4,350,631, U.S. Pat.No. 4,383,946 and U.S. Pat. No. 4,414,155 all assigned to Merck andCompany, Inc. and hereby incorporated by reference.

The general synthesis description depicted above in the Flow Sheetsshows a protected 1-hydroxyethyl substitution on the 6-position of thecarbapenem. After final deprotection, a 1-hydroxyethyl substituent isobtained, which is preferred in most cases. However, it has been beenfound that with certain 2-side-chain selections, the ultimate balance offavorable properties in the overall molecule may be enhanced byselection of the 6-(1-fluoroethyl) moiety instead. Preparation of6-fluoroalkyl compounds within the scope of the present invention iscarried out in a straightforward manner using techniques well known inthe art of preparing carbapenem antibacterial compounds. See, e.g., J.G. deVries et al., Heterocycles, 23 (8), 1915 (1985); BE 900 718 A(Sandoz) and Japanese Patent Pub. No. 6-0163-882-A (Sanruku Ocean).

In preferred compounds of Formula I, either R¹ or R² is hydrogen andmore preferably, R¹ is hydrogen. In the most preferred case, R¹ ishydrogen and R² is (R)--CH₃ CH(OH)--or (R)--CH₃ CH(F)--. While R=H isusually preferred, there are instances in which R=CH₃ may provideimproved chemical stability, water solubility, or pharmacokineticbehavior. The substituent R=CH₃ may be of either configuration, i.e.,the α or β-stereoisomer. Additionally, in preferred compounds, R^(a) inthe 5-position of the biphenyl is other than hydrogen.

Suitable R^(a) are described above in the text associated with FormulaI. Among preferred R^(a) are C₁₋₄ alkyl mono-substituted with hydroxy,such as, hydroxymethyl; formyl; carboxy, such as, --COOK; carbamoyl,such as, --CONH₂ ; hydroxyiminomethylene, such as, --CH═NOH or cyano.

In regard to this preferred substitution, one or more hydroxymethylgroups may be obtained on the biphenyl ring as desired utilizing wellknown synthetic methods. For example where biphenyl is producedaccording to Flow Sheet AE, then a methyl group, as a precursorsubstituent, is substituted on starting materials AE1 and/or AE2 in theappropriate positions by well known means and the starting materialsreacted to a corresponding B1. Subsequently, the methyl substituent ofB1 may be oxidized e.g. to a carboxylic acid group with chromiumtrioxide or to bromomethyl group with N-bromosuccinimide. This oxidationof the methyl precursor substituent, may be advantageously performedprior to substituting the biphenyl on the azetidin-2-one as theoxidizing conditions may be incompatible with either the azetidin-2-oneor the subsequent carbapenem. The carboxylic acid group may be convertedto a hydroxymethyl group utilizing a borane tetrahydrofuran complex andthe bromomethyl by conversion to acetoxymethyl group with potassiumacetate followed by hydrolysis. As another example where the biphenyl isproduced according to Flow Sheets AA through AD, an amino substituentmight be converted to a halogen which is then transformed to acarboxylic acid moiety and subsequently to hydroxymethyl group asdescribed above and all by well known reactions.

The preferred formyl substitution on the biphenyl may be obtained fromthe hydroxymethyl substitution of B4 by a Swern oxidation. For example,isomeric B4 is oxidized in methylene chloride at from -70° C. to roomtemperature employing triethylamine and as the active agent, oxalylchloride-dimethyl sulfoxide. Obviously, the position of the resultantformyl substitution will depend upon the position of the hydroxymethylsubstitution in isomeric B4.

The preferred --CH═NOH substitution on the biphenyl may be convenientlyobtained from the formyl substitution just described. This isaccomplished simply by exposing the formyl substituted compound tohydroxylamine in an appropriate solvent at room temperature.

The preferred cyano substitution on the biphenyl may be obtained fromthe --CH═NOH substitution just described. The --CH═NOH substitutedcompound is dehydrated with triflic anhydride and triethylamine in asolvent at -70° C.

The preferred --COOK substitution on the biphenyl may be obtained fromthe hydroxymethyl substituted B3 or isomeric B3 described above. Forexample, an isomeric B3 is oxidized with Jones reagent to convert thehydroxymethyl substituent to the carboxylic acid group. The oxidationwith Jones reagent may be incompatible with the carbapenem and thus isoptimally performed before ring closure. Prior to ring closure, thecarboxylic acid group is protected as its allyl ester to permitcyclization of the carbapenem. Protection is carried out by alkylatingwith allyl bromide and triethylamine. Deprotection following cyclizationis carried out in a palladium catalyzed reaction, in a solutioncontaining potassium 2-ethylhexanoate, as described in McCombie andJeffrey, J. Org. Chem., 47, 2505 (1983). Deprotection in such a solutionyields the desired potassium salt.

The preferred carbamoyl, --CONH₂, may be obtained from B3 by oxidizingthe hydroxymethyl group with Jones reagent to the correspondingcarboxylic acid group as described above. This carboxylic acidsubstituent is converted to carboxamide group (--CONH₂) by sequentiallycontacting with 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimidehydrochloride, 1-hydroxybenzotriazole, and ammonia in an organic solventat room temperature. Substituted amides may of course be obtained byreplacing ammonia with the corresponding substituted amine. In contrastto the carboxyl substitution, this carbamoyl group requires noprotection for the conditions of carbapenem cyclization.

Compounds substituted with the preferred R^(a) of Type II just describedmay also be obtained by employing the synthesis shown in Flow Sheet C.In this case, the synthetic transformations just described may becarried out on intermediate C3 prior to attachment of the biphenylside-chain to carbapenem or on C4 after such attachment.

In the preparation methods described above, the carboxyl group at the3-position and the hydroxyl group at the 8-position of the carbapenemremain blocked by protecting groups until the penultimate product isprepared. Deblocking may be carried out in a conventional manner. Forcompounds prepared according to Flow Sheet B, deprotection may becarried out in a palladium catalyzed reaction in a soution containingpotassium 2-ethylhexanoate and 2-ethylhexanoic acid or, alternatively,another suitable nucleophile such as pyrrolidine. Alternatively, forthose prepared via Flow Sheet C, deprotection is conducted sequentially.Thus, compound C4 is exposed initially to aqueous acidic conditions,acetic acid or dilute HCl or the like, in an organic solvent such astetrahydrofuran at 0° C. to ambient temperature for from a few minutesto several hours. The resulting desilylated carbapenem may be isolatedby conventional techniques, but is more conveniently taken into thefinal deprotection process. Thus, addition of an inorganic base such asNaHCO₃ or KHCO₃ and 10% Pd/C followed by hydrogenation provides for theremoval of the p-nitrobenzyl protecting group and the formation of thefinal compound of Formula I.

With reference to the above definitions, "alkyl" means a straight orbranched chain aliphatic hydrocarbon radical.

The term "heteroatom" means N, S, or O, selected on an independentbasis.

The term "heteroaryl" has been defined herein, in relation to the R^(X)group, to have a specific and limited meaning, being only monocyclic. Itis required that the monocyclic heteroaryl have at least one nitrogenatom, and optionally at most only one additional oxygen or sulfurheteroatom may be present. Heteroaryls of this type are pyrrole andpyridine (1 N); and oxazole, thiazole or oxazine (1 N+1 O or 1 S). Whileadditional nitrogen atoms may be present together with the firstnitrogen and oxygen or sulfur, giving, e.g., a thiadiazole (2N's+1S),the preferred heteroaryls are those where only nitrogen heteroatoms arepresent when there is more than one. Typical of these are pyrazole,imidazole, pyrimidine and pyrazine (2 N's) and triazine (3 N's).

The heteroaryl group of R^(X) is always optionally mono-substituted byR^(q), defined above, and substitution can be on one of the carbon atomsor one of the heteroatoms, although in the latter case certainsubstitutent choices may not be appropriate.

Listed in Tables I and II are specific compounds of the instantinvention:

                                      TABLE I                                     __________________________________________________________________________     ##STR16##                                                                                                     Ra                                           #  R   R.sup.2   M  R.sup.a      position                                     __________________________________________________________________________     1 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OCH.sub.3    5                                             2 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OCH.sub.2 CO.sub.2 Na                                                                      5                                             3 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OCH.sub.2 CH.sub.2 OH                                                                      5                                             4 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CF.sub.3     5                                             5 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         F            5                                             6 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          Cl           5                                             7 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          Br           5                                             8 H   CH.sub.2 OH                                                                             K.sup.+                                                                          I            5                                             9 β-CH.sub.3                                                                   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OH           5                                            10 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OCOCH.sub.3  5                                            11 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OCONH.sub.2  5                                            12 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SCH.sub.3    5                                            13 H   (R)CH(F)CH.sub.3                                                                        K.sup.+                                                                          SOCH.sub.3   5                                            14 β-CH.sub.3                                                                   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SO.sub.2 CH.sub.3                                                                          5                                            15 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SCH.sub.2 CH.sub.2 OH                                                                      5                                            16 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SOCH.sub.2 CH.sub.2 OH                                                                     5                                            17 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SO.sub.2 CH.sub.2 CH.sub.2 OH                                                              5                                            18 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SO.sub.2 NH.sub.2                                                                          5                                            19 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SO.sub.2 N(CH.sub.3).sub.2                                                                 5                                            20 H   CF.sub.2 CH.sub.3                                                                       K.sup.+                                                                          NHCHO        5                                            21 β-CH.sub.3                                                                   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          NHCOCH.sub.3 5                                            22 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          NHCO.sub.2 CH.sub.3                                                                        5                                            23 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          NHSO.sub.2 CH.sub.3                                                                        5                                            24 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CN           5                                            25 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHO          5                                            26 H   CH.sub.2 OH                                                                             K.sup.+                                                                          COCH.sub.3   5                                            27 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          COCH.sub.2 OH                                                                              5                                            28 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHNOH        5                                            29 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHNOCH.sub.3 5                                            30 α-CH3                                                                       (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHNOCH.sub.2 CO.sub.2 H                                                                    5                                            31 α-CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                       K.sup.+                                                                          CHNOCMe.sub.2 CO.sub.2 H                                                                   5                                            32 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHNOCMe.sub.2 CO.sub.2 Me                                                                  5                                            33 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CO.sub.2 CH.sub.2 CH.sub.2 OH                                                              5                                            34 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONH.sub.2   5                                            35 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHCH.sub.3 5                                            36 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CON(CH.sub.3).sub.2                                                                        5                                            37 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHCH.sub.2 CN                                                                            5                                            38 β-CH.sub.3                                                                   CF.sub.2 CH.sub.3                                                                       K.sup.+                                                                          CONHCH.sub.2 CONH.sub.2                                                                    5                                            39 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHCH.sub.2 CO.sub.2 H                                                                    5                                            40 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CONHOH       5                                            41 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHOCH.sub.3                                                                              5                                            42 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                      tetrazolyl                                                                       5                                                                          43 H   CH.sub.2 OH                                                                             K.sup.+                                                                          CO.sub.2 Na  5                                            44 H   (R)CH(OH)CF.sub.3                                                                       K.sup.+                                                                          SCF.sub.3    5                                            45 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          PO.sub.3 NaH 5                                            46 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHSO.sub.2 Ph                                                                            5                                            47 β-CH.sub.3                                                                   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHSO.sub.2 NH.sub.2                                                                      5                                            48 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SO.sub.3 Na  5                                            49 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SO.sub.2 NHCN                                                                              5                                            50 β-CH.sub.3                                                                   (R)CH(F)CH.sub.3                                                                        K.sup.+                                                                          SO.sub.2 NHCONH.sub.2                                                                      5                                            51 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHCHCN       5                                            52 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHCHCONH.sub.2                                                                             5                                            53 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHCHCO.sub.2 Na                                                                            5                                            54 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CCCONH.sub.2 5                                            55 β-CH.sub.3                                                                   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CCCN         5                                            56 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CH.sub.2 OH  4'                                           57 H   CH.sub.2 CH.sub.3                                                                       K.sup.+                                                                          CH.sub.2 N.sub.3                                                                           5                                            58 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CH.sub.2 CO.sub.2 Na                                                                       5                                            59 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SOCH.sub.3   5                                            60 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SO.sub.2 CH.sub.3                                                                          5                                            61 H   (R)CH(OH)CH.sub. 3                                                                      Na.sup.+                                                                         NHCHO        5                                            62 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         NHCOMe       5                                            63 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         COCH.sub.3   5                                            64 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         COCF.sub.3   5                                            65 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         COCH.sub.2 CONH.sub.2                                                                      5                                            66 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CH.sub.2 CONH.sub.2                                                                        5                                            67 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CONHCH.sub.2 CONH.sub.2                                                                    5                                            68 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SCF.sub.3    5                                            69 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CONHSO.sub.2 NH.sub.2                                                                      5                                            70 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCH.sub.2 CH.sub.2 OH                                                                      4'                                           71 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCH.sub.2 CH.sub.2 OH                                                                      5'                                           72 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCOCH.sub.3  4'                                           73 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCOCH.sub.3  3'                                           74 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCONH.sub.2  4'                                           75 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SCH.sub.2 CH.sub.2 OH                                                                      5'                                           76 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SCH.sub.2 CH.sub.2 OH                                                                      4'                                           77 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SCH.sub.2 CH.sub.2 OH                                                                      3'                                           78 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CHO          4'                                           79 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CHO          3'                                           80 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CHO          5,4'                                         81 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         COCH.sub.2 OH                                                                              4'                                           82 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SO.sub.2 N(CH.sub.2 CH.sub.2 OH).sub.2                                                     5                                            83 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          ##STR17##   5                                            84 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          ##STR18##   5                                            85 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          ##STR19##   5                                            86 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          CO.sub.2 Me 5                                            87 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         F            3'                                           88 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CH.sup.t CHCN                                                                              4'                                           89 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CH.sup.t CHCONH.sub.2                                                                      4'                                           90 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CN           4'                                           91 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OH           3'                                           92 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OH           4'                                           93 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CH.sub.2 SMe 4'                                           94 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCONH.sub.2  3'                                           95 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SOMe         4'                                           96 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SO.sub.2 CH.sub.3                                                                          4'                                           97 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SMe          4'                                           98 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CH.sup.c CHCN                                                                              4'                                           99 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OH           3',4'                                        100                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OH           3',4',5'                                     101                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OH           5,3',4'                                      102                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         F            5,4'                                         103                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         F            5,3'                                         104                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SMe          5,3'                                         105                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SMe          5,4'                                         __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________     ##STR20##                                                                                    R.sup.a                                                       R.sup.1                                                                            R.sup.2    5     5'   4'    3'                                           __________________________________________________________________________    H    (R)CH(OH)CH.sub.3                                                                        CHO   H    OH    H                                            H    (R)CH(OH)CH.sub.3                                                                        CHO   H    F     H                                            H    (R)CH(OH)CH.sub.3                                                                        CHO   CHO  F     H                                            H    (R)CH(OH)CH.sub.3                                                                        SCH.sub.3                                                                           H    OH    H                                            H    (R)CH(OH)CH.sub.3                                                                        SCH.sub.3                                                                           H    SOCH.sub.3                                                                          H                                            H    (R)CH(OH)CH.sub.3                                                                        SCH.sub.3                                                                           CHO  H     H                                            H    (R)CH(OH)CH.sub.3                                                                        SCH.sub.3                                                                           H    CH.sub.2 OH                                                                         H                                            H    (R)CH(OH)CH.sub.3                                                                        CONH.sub.2                                                                          H    CHO   H                                            H    (R)CH(OH)CH.sub.3                                                                        CONH.sub.2                                                                          F    CHO   H                                            H    (R)CH(OH)CH.sub.3                                                                        CONH.sub.2                                                                          H    CH.sub.2 OH                                                                         H                                            β-CH.sub.3                                                                    (R)CH(OH)CH.sub.3                                                                        CONH.sub.2                                                                          H    SOCH.sub.3                                                                          H                                            H    CH.sub.2 OH                                                                              SCH.sub.3                                                                           H    CHO   H                                            H    (R)CH(OH)CH.sub.3                                                                        CN    H    SOCH.sub.3                                                                          H                                            H    (R)CH(OH)CH.sub.3                                                                        CN    H    CONH.sub.2                                                                          H                                            H    (R)CH(OH)CH.sub.3                                                                        CN    H    OH    OH                                           H    (R)CH(OH)CH.sub.3                                                                        CN    H    CHO   H                                            H    (R)CH(OH)CH.sub.3                                                                        SO.sub.2 CH.sub.3                                                                   H    CHO   H                                            H    (R)CH(OH)CH.sub.3                                                                        SO.sub.2 CH.sub.3                                                                   H    CONH.sub.2                                                                          H                                            __________________________________________________________________________

The carbapenem compounds of the present invention are useful per se andin their pharmaceutically acceptable salt and ester forms in thetreatment of bacterial infections in animal and human subjects. The term"pharmaceutically acceptable ester or salt" refers to those salt andester forms of the compounds of the present invention which would beapparent to the pharmaceutical chemist, i.e., those which are non-toxicand which would favorably affect the pharmacokinetic properties of saidcompounds, their palatability, absorption, distribution, metabolism andexcretion. Other factors, more practical in nature, which are alsoimportant in the selection, are cost of the raw materials, ease ofcrystallization, yield, stability, hygroscopicity, and flowability ofthe resulting bulk drug. Conveniently, pharmaceutical compositions maybe prepared from the active ingredients in combination withpharmaceutically acceptable carriers. Thus, the present invention isalso concerned with pharmaceutical compositions and methods of treatingbacterial infections utilizing as an active ingredient the novelcarbapenem compounds of the present invention.

The pharmaceutically acceptable salts referred to above may take theform --COOM. The M may be an alkali metal cation such as sodium orpotassium. Other pharmaceutically acceptable cations for M may becalcium, magnesium, zinc, ammonium, or alkylammonium cations such astetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium,meglumine, triethanolhydroammonium, etc.

The pharmaceutical acceptable esters of the novel carbapenem compoundsof the present invention are such as would be readily apparent to amedicinal chemist, and include, for example, those described in detailin U.S. Pat. No. 4,309,438, Column 9, line 61 to Column 12, line 51,which is incorporated herein by reference. Included within suchpharmaceutically acceptable esters are those which are hydrolyzed underphysiological conditions, such as pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, and those described in detail inU.S. Pat. No. 4,479,947, which is incorporated herein by reference.

The novel carbapenem compounds of the present invention may take theform COOM, where M is a readily removable carboxyl protecting group.Such conventional blocking groups consist of known ester groups whichare used to protectively block the carboxyl group during the synthesisprocedures described above. These conventional blocking groups arereadily removable, i.e., they can be removed, if desired, by procedureswhich will not cause cleavage or other disruption of the remainingportions of the molecule. Such procedures include chemical and enzymatichydrolysis, treatment with chemical reducing or oxidizing agents undermild conditions, treatment with a transistion metal catalyst and anucleophile, and catalytic hydrogenation. Examples of such esterprotecting groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethyl,allyl, benzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl,p-methoxybenzyl, acetonyl, o-nitrobenzyl, and 4-pyridylmethyl.

The compounds of the present invention are valuable antibacterial agentsactive against various Gram-positive and to a lesser extentGram-negative bacteria and accordingly find utility in human andveterinary medicine. The antibacterials of the invention are not limitedto utility as medicaments; they may be used in all manner of industry,for example: additives to animal feed, preservation of food,disinfectants, and in other industrial systems where control ofbacterial growth is desired. For example, they may be employed inaqueous compositions in concentrations ranging from 0.1 to 100 parts ofantibiotic per million parts of solution in order to destroy or inhibitthe growth of harmful bacteria on medical and dental equipment and asbactericides in industrial applications, for example in waterbasedpaints and in the white water of paper mills to inhibit the growth ofharmful bacteria.

The compounds of this invention may be used in any of a variety ofpharmaceutical preparations. They may be employed in capsule, powderform, in liquid solution, or in suspension. They may be administered bya variety of means; those of principal interest include: topically orparenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents.Alternatively, the active ingredient may be in powder form forreconstitution, at the time of delivery, with a suitable vehicle, suchas sterile water. Topical applications may be formulated in hydrophobicor hydrophilic bases as ointments, creams, lotions, paints, or powders.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated as well as the route andfrequency of administration, the parenteral route by injection beingpreferred for generalized infections. Such matters, however, are left tothe routine discretion of the therapist according to principles oftreatment well known in the antibacterial art. Another factorinfluencing the precise dosage regimen, apart from the nature of theinfection and peculiar identity of the individual being treated, is themolecular weight of the chosen species of this invention.

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from 0.1% to 99% of active material, the preferredrange being from about 10-60%. The composition will generally containfrom about 15 mg to about 1500 mg of the active ingredient; however, ingeneral, it is preferably to employ a dosage amount in the range of fromabout 250 mg to 1000 mg. In parenteral administration, the unit dosageis usually the pure compound I in sterile water solution or in the formof a soluble powder intended for solution.

The preferred method of administration of the Formula I antibacterialcompounds is parenteral by i.v. infusion, i.v. bolus, or i.m. injection.

For adults, 5-50 mg of Formula I antibacterial compounds per kg of bodyweight given 2, 3, or 4 times per day is preferred. Preferred dosage is250 mg to 1000 mg of the Formula I antibacterial given two (b.i.d.)three (t.i.d.) or four (q.i.d.) times per day. More specifically, formild infections a dose of 250 mg t.i.d. or q.i.d. is recommended. Formoderate infections against highly susceptible gram positive organisms adose of 500 mg t.i.d. or q.i.d. is recommended. For severe,life-threatening infections against organisms at the upper limits ofsensitivity to the antibiotic, a dose of 1000 mg t.i.d. or q.i.d. isrecommended.

For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 timesper day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usuallyrecommended.

Antibacterial compounds of Formula I are of the broad class known ascarbapenems or 1-carbadethiapenems. Naturally occuring carbapenems aresusceptible to attack by a renal enzyme known as dehydropeptidase (DHP).This attack or degradation may reduce the efficacy of the carbapenemantibacterial agent. The compounds of the present invention, on theother hand, are significantly less subject to such attack, and thereforemay not require the use of a DHP inhibitor. However, such use isoptional and contemplated to be part of the present invention.Inhibitors of DHP and their use with carbapenem antibacterial agents aredisclosed in the prior art [see European patent applications No.79102616.4 filed July 24, 1979 (Pat. No. 0 007 614); and No. 82107174.3,filed Aug. 9, 1982 (Publication No. 0 072 014)].

The compounds of the present invention may, where DHP inhibition isdesired or necessary, be combined or used with the appropriate DHPinhibitor as described in the aforesaid patents and publishedapplication. Thus, to the extent that the cited European patentapplications 1 define the procedure for determining DHP susceptibilityof the present carbapenems and 2 disclose suitable inhibitors,combination compositions and methods of treatment, they are incorporatedherein by reference. A preferred weight ratio of Formula I compound: DHPinhibitor in the combination compositions is about 1:1. A preferred DHPinhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid or a useful salt thereof.

Unless otherwise indicated, all of the temperatures in the workingexamples which follow are in degrees Celsius (°C.).

EXAMPLE 1 ##STR21##

Step (a)

To a stirred partial solution of 2.13 g (7.68 mmole) of carboxylic acidderivative 1B, prepared according to D. J. Byron, et al, J. Chem. Soc.(C), 840 (1966), in 40 cc of freshly distilled, dry THF at ambienttemperature was added slowly and cautiously a solution of 1Mborane-tetrahydrofuran complex in THF (15.4 mL, 15.4 mmole). Theresulting mixture was stirred overnight at ambient temperature under aninert atmosphere of nitrogen and then carefully quenched with methanol.The solution was evaporated under reduced pressure and the residue driedin vacuo to give ca. 2 g (100%) of crude alcohol 1C which may be usedwithout further purification.

Purification of 1C can be formed on silica gel utilizing CH₂ Cl₂ --Et₂ O(20:1) as the eluant; NMR (CDCl₃) δ: 4.74(s, --CH₂ O--), 7.42-7.72 (m,8Ar-e,uns/H/ ).

Step (b)

To stirred solution of 2.3 g (8.9 mmole) of carbinol 1C from step (a) in25 mL of sieve dried DMF at ambient temperature was added 1.35 g (13.4mmole) of triethylamine and 2.02 g (13.4 mmole) of t-butyldimethylsilylchloride. The resulting mixture was stirred at room temperature under aninert atmosphere of nitrogen for 1.5 hours. After this time, the mixturewas partitioned between ET₂ O/ice-H₂ O/2N HCl and the organic phase wasseparated. It was washed twice with ice-H₂ O and then with a saturatedsolution of sodium chloride; dried with anhyrous soldium sulfate,filtered, and evaporated.

Purification by column chromatography on silica gel eluting withpetroleum-ether (30°-60° C.) --CH₂ Cl₂ (10:1) provided 3.16 g (94%) ofproduct 3; NMR (CDCl₃) δ: 0.12 (s, Si(CH₃)₂), 0.96 (s, SiC(CH₃)₃, 4.78(s, OCH₂), 7.32-7.74 (m, Ar-H).

EXAMPLE 2 ##STR22##

A stirred solution of 1D (562 mg, 1.49 mmole) in 5 mL freshly distilled,dry THF was treated with 54.5 mg (2.23 mmole) of magnesium turnings and5 μl dibromoethane at ambient temperature in an inert atmosphere ofnitrogen for 5.5 hours. This solution of the Grignard reagent was thenadded to a solution of pyridylthio ester derivative 2A (527.8 mg, 0.75mmole) in 5 mL dry THF at 0° C. under a nitrogen atmosphere. Theresulting mixture was stirred at 0° C. for 15 minutes and thenpartitioned between EtOAc/ice/1M NH₄ Cl(aq.) and the organic phaseseparated. It was washed with ice-H₂ O/5N NaOH and then saturated sodiumchloride solution, dried with anhydrous sodium sulfate, filtered, andevaporated under reduced pressure.

Purification by plate layer chromatography (PLC) eluting with Et₂ O gave501.2 mg (75%) of 2B; IR(CH₂ Cl₂) 1745, 1685, 1610 cm⁻¹.

EXAMPLE 3 ##STR23##

A mixture of 501.2 mg (0.56 mmole) of phosphorane 2B, prepaared inExample 2, and 160 μL concentrated sulfuric acid in 8 mL of methanol wasstirred magnetically at 0° C. in an inert atmosphere of nitrogen for 1.0hour. After this time, the mixture was partitioned between EtOAc/ice-H₂O/satd. NaHCO₃ (aq.) solution and the organic phase was separated,washed with saturated sodium chloride solution, dried over sodiumsulfate, filtered, evaporated, and dried in vacuo to give 443 mg (>100%)of crude product 3A, which could be used without further purification;IR(CH₂ Cl₂) 1745, 1675, 1610 cm⁻¹.

EXAMPLE 4 ##STR24##

A stirred solution of crude phosphorane 3A (437.4 mg, 0.56 mmole),prepared in Example 3, in 30 mL of dry xylenes containing a crystal ofhydroquinone was heated at 140° C. under an atmosphere of nitrogen for84 minutes. After this time the mixture was let cool and then it wasevaporated under reduced pressure.

Purification of the residue by PLC [one development CH₂ Cl₂ /EtOAc(5:1)] gave 190.5 mg (68%) of 4A as an oil; IR(CH₂ Cl₂) 1770, 1750, 1725cm⁻¹ ; NMR(CDCl₃) δ: 1.51 (d, CH₃), 3.25 (dd, 1-H-1), 3.47 (dd, 1-H-1),3.45 (dd, 1-H-6), 4.31 (dt, 1-H-5), 4.76 (bs, 2H, --CH₂ OH), 7.3-7.58(m, 8-ArH); UV: λ_(max) ^(dioxane) 307 nm.

EXAMPLE 5 ##STR25##

To a stirred solution of 19 μL (0.22 mmole) of oxalyl chloride in 1.5 mlanhydrous CH₂ Cl₂ at -78° C. under a N₂ atmosphere was added 19.7 μL(0.27 mmole) of anhydrous DMSO. The resulting solution was stirred at-78° C. for 4 minutes and then a solution of 100 mg (0.20 mmole) ofalcohol 4A in 1.0 mL anhydrous CH₂ Cl₂ was added. The resulting yellowsolution was stirred at -78° C. for 15 minutes and then 76 μL (0.55mmole) of triethylamine was added. The resulting solution was stirred at-78° C. for 25 minutes and then partitioned between EtOAc and ice/2.0Naqueous HCl solution. The organic phase was separated, washed withbrine, dried with anhydrous Na₂ SO₄, filtered and concentrated undervacuum to provide 94.4 mg of aldehyde 8 as a yellow film; IR(CH₂ Cl₂):1780, 1745, 1720, 1700 cm⁻¹ ; 300 MHz ¹ H-NMR(CDCl₃) δ: 1.50 (d, J=8.2Hz, CH₃), 3.31 (m, 2-H-1), 3.45 (dd, J=2.8, 8.4 Hz, 1-H-6) 4.31 (td,1-H-5), 4.67 (m, 1-H-8 and CH₂ CH═CH₂), 5.29 (m, CH₂ CH═CH₂), 5.90 (m,CH₂ CH═CH₂), 7.37-7.98 (m, phenyl-H), 10.08 (s, --CHO).

EXAMPLE 6 ##STR26##

To a stirred solution of 94.4 mg (0.19 mmole) of aldehyde 5A in 4 mLanhydrous acetonitrile at 0° C. under a N₂ atmosphere was added 102 mg(0.34 mmole) of cyanomethylene triphenylphosphorane. The resultingsolution was stirred at room temperature for 3 hours and thenconcentrated under vacuum to provide a yellow film which was purified byPLC (2×1000 μ 20×20 cm silica gel GF; 1:1, hexanes: EtOAc) to providetwo products: trans 6A, 44.6 mg of a clear film; IR(CH₂ Cl₂): 2210,1780, 1745, 1720 cm⁻¹ ; 300 MHz NMR (CDCl₃) δ: 1.50 (d, J=6.2 Hz, CH₃),3.30 (m, 2H-1), 3.44 (dd, J=2.9, 8.4 Hz, CHCHC═O), 4.32 (td, CHCHCH₂),4.65 (m, 1H-8 and CH₂ CH═CH₂), 5.30 (m, CH₂ CH═CH₂), 5.87 (m, CH₂CH═CH₂), 5.92 (d, J=16.5 Hz, CH═CHCN), 7.27-7.63 (m, phenyl-H andCH═CHCN). UV: λ_(max) ^(dioxane) 309 nm; and cis 6A: 22.3 mg of a clearfilm; 300 MHz NMR (CDCl₃): δ: 5.48 (d, J=12.1 Hz, CH═CHCN), 7.68 (d,J=12.1 Hz, CH═CHCN).

EXAMPLE 7 ##STR27##

To a stirred solution of 100.6 mg (0.2 mmole) of 4A in 6 ml of CH₂ Cl₂--EtOAc (1:1) at ambient temperature was added 31.5 mg (0.12 mmole) oftriphenylphosphine, 46.2 mg (0.04 mmole) of tetrakistriphenylphosphinepalladium, 31.7 mg (0.22 mmole) 2-ethylhexanoic acid, and 440 μL of 0.5Mpotassium 2-ethylhexanoate in EtOAc (0.22 mmole). The resulting mixturewas stirred at ambient temperature under a nitrogen atmosphere for 2.5hours. The separated product was triturated with 8 mL of Et₂ O-EtOAc(1:1) and collected by centrifugation and decantation of thesupernatant. The solid was washed similarly with 10 mL Et₂ O and driedto give 109.4 mg of crude product.

Purified by reverse phase-plate layer chromotography on two-1000μ plates[one development H₂ O-MeCN (5:1)] to give after extraction with MeCN--H₂O (4:1) and lyophilization 37.6 mg (45%) of 7A; IR (Nujol) 1750 and 1595cm⁻¹ ; NMR (D₂ O) δ: 1.32 (d, Me), 3.12 (dd, 1-H-1), 3.48 (app dd,1-H-1), 3.54 (app dd, 1-H-6), 4.34 (m, H-5 and H-8), 4.72 (s, 2H), 7.6(m, 8-Ar-H); UV: λ_(max) H₂ O 297 nm, 257 nm.

EXAMPLE 8 ##STR28##

Step (a)

To a stirred solution of 3-nitro-4-amino-biphenyl (13.85 g, 64.7 mmole)[prepared according to a the procedures described in C. Dell 'Erba, G.Garbarino, and G. Guanti, Tetrahedron, 27, 113 (1971).] in 230 mLdioxane and 77 mL H₂ O cooled in an ice-H₂ O bath was added sequentially12.9 mL 5N NaOH (aq.) (64.7 mmole) and then dropwise 12.41 g (77.7mmole) bromine. When the addition was complete, the ice-H₂ O bath wasremoved, and the mixture stirred further for 2 hours. After this time,the mixture was concentrated under high vacuum, H₂ O added, and theinsoluble material collected by suction filtration and washed with H₂ O.The solid was dried in vacuo to give 19.6 g of crude product.

Recrystallization from MeOH-CH₂ Cl₂ -pet. ether gave only 8.78 g (46.5%)of 3-bromo-4-amino-5-nitro-biphenyl; NMR (CDCl₃) δ: 6.65 (bs, 2 NH),7.44 (m, 5 Ar-H), 7.98 (d, l-Ar-H), and 8.38 (d, l-Ar-H).

Chromatography on silica gel of the mother liquors using CH₂ Cl₂ -pet.ether (1:1) as eluant gave an additional 7.6 g of product for a combinedyield of 86.7%.

EXAMPLE 9 ##STR29##

To a stirred solution of 759 mg (11 mmole) of sodium nitrite in 15 mLconcentrated sulfuric acid chilled in an ice-H₂ O bath was added asolution of 2.92 g (10 mmole) of biphenylamine derivative from Example 9in 30 mL hot glacial HOAc. The resulting mixture was stirred at ice-H₂ Obath temperature for 20 minutes.

The ice-H₂ O bath was removed, 1.27 g (20 mmole) copper powder added,and the mixture stirred further for 2 hours. The insolubles were removedby suction filtration through a preformed pad of celite and washed withEt₂ O. The filtrate was partitioned between Et₂ O/ice-H₂ O/5N NaOH andthe organic phase was separated, washed with saturated NaCl solution,dried Na₂ SO₄, filtered, and evaporated.

The residue was purified by chromatography on 50 grams of EM-60 silicagel eluted with petroleum ether-CH₂ Cl₂ (2:1) to give 2.2 g (80%) of3-bromo-5-nitro-biphenyl; NMR (CDCl₃) δ: 7.54 (m, 5 Ar-H), 8.05 (d, 1Ar-H). 8.34 (d, 1 Ar-H), and 8.38 (d, 1 Ar-H).

EXAMPLE 10 ##STR30##

A stirred mixture of 7.62 g (27.5 mmole) of 3-bromo-5-nitrobiphenyl and18.62 g (82.5 mmole) of stannous chloride dihydrate in 150 mL ofabsolute ethanol was refluxed under a nitrogen atmosphere for 1.5 hours.After this time, the mixture was concentrated and partitioned betweenEt₂ O/ice/5N NaOH. The organic phase was separated, washed withsaturated NaCl solution, dried over Na₂ SO₄, filtered, and evaporated.

The product was purified by chromatography on silica gel with CH₂ Cl₂-petroleum ether (1:1) to give 5.9 g (87%) of 3-bromo-5 aminobiphenyl;NMR (CDCl₃) δ: 3.8 (bs 2NH), 6.82 (m, 1Ar-e,uns/H/ ), 7.15 (t, 1Ar-H),7.48 (m, 6Ar-H).

EXAMPLE 11 ##STR31##

To a stirred solution of 1.08 g (15.6 mmole) of NaNO₂ in 10 mL conc. H₂SO₄ cooled in an ice-H₂ O bath was added dropwise a solution of 3.67 g(14.9 mmole) of 3-bromo-4-aminobiphenyl in 40 mL HOAc. When the additionwas complete, the mixture was stirred further for 10 minutes at 0° C.,and then 4.0 g (21.7 mmole) of KPF₆ in 43 mL H₂ O was added. Theresulting mixture was stirred cold for 10 minutes and the separatedproduct collected by suction filtration; washed well with cold H₂ O andthen with 80 mL Et₂ O-MeOH (4:1); dried in vacuo overnight to give 5.87g (97%) of diazonium hexafluorophosphate derivative; mp 157° C. (dec);IR (Nujol) 2295 cm⁻¹ ; NMR (d₆ -DMSO) δ: 7.66 (m, 3Ar-H), 7.88 (m, 2Ar-H), 8.88 (m, 1Ar-H), 9.0 (m, 1Ar-H), and 9.16 (m, 1Ar-H).

EXAMPLE 12 ##STR32##

A stirred suspension of 4.04 g (10 mmole) of diazonium salt in 40 mLdecane under a nitrogen atmosphere was immersed in a 170° C. oil bathfor 10 minutes. The mixture was allowed to cool and then filteredthrough celite and washed with Et₂ O. The filtrate was partitionedbetween Et₂ O/ice-H₂ O/saturated NaHCO₃ (aq.) solution and the organicphase separated, washed with saturated NaCl solution, dried over Na₂SO₄, filtered, and evaporated.

The residue was purified by chromatography on silcia gel with petroleumether solvent to give 2.51 g (100%) of 3-bromo-5-fluorobiphenyl; NMR(CDCl₃) δ: 7.2 (m, 2Ar-H) and 7.48 (m, 6Ar-H); MS: m/e 252, 250 (M⁺).

EXAMPLE 13 ##STR33##

As previously described in Example 12, 1.24 g (5 mmole) of3-bromo-5-aminobiphenyl was diazotized with 380 mg (5.5 mmole) of NaNO₂in 4 mL conc. H₂ SO₄ and 10 mL HOAc. The the stirred mixture was added10 mL H₂ O and it was heated at 70° C. under a nitrogen atmosphere for1.25 hours.

The cooled mixture was partitioned between Et₂ O-H₂ O, and the organicphase separated, washed with H₂ O (2×), then ice/saturated, NaHCO₃ (aq.)solution and saturated NaCl solution; dried over Na₂ SO₄, filtered andevaporated.

The residue was purified by column chromatography on silica gel with CH₂Cl₂ -petroleum ether (1:1) and CH₂ Cl₂ -petroleum ether (3:1) to provide995 mg (80%) of 3-bromo-5-hydroxy-biphenyl; NMR (CDCl₃) δ: 5.32 (bs,OH), 7.02 (m, Ar-H) and 7.4 (m, Ar-H).

EXAMPLE 14 ##STR34##

To a stirred solution of 995 mg (4 mmole) of 3-bromo-4-hydroxybiphenylin 10 mL sieve dried DMF at ambient temperature was added 173.3 mg (4.4mmole) of 61.1% mineral oil dipersion of NaH. The resulting mixture wasstirred at room temperature under a nitrogen atmosphere for 10 minutesand 1.71 g (12 mmole) of neat MeI was added. The mixture was stirredfurther at ambient temperature for 0.5 hour.

The mixture was poured onto ice-H₂ O and extracted with Et₂ O. Theextract was washed with ice-H₂ O (2×), and then saturated NaCl solution;dried over Na₂ SO₄, filtered, and evaporated.

The residue was purified by silica gel chromatography with petroleumether solvent to give 842 mg (80%) of 3-bromo-5-methoxybiphenyl; NMR(CDCl₃) δ: 3.87 (s, OCH₃), 7.07 (m, 2Ar-H), 7.48 (m, 6Ar-H).

EXAMPLE 15 ##STR35##

To a stirred solution of 372 mg (1.5 mmole) of 3-bromo-5-hydroxybiphenyland 339.1 mg (2.25 mmole) of t-butyldimethylsilyl chloride in 4 mL sievedried DMF at ambient temperature under a nitrogen atmosphere was added227.7 mg (2.25 mmole) of triethylamine. The resulting mixture wasstirred further for 1.75 hours.

The mixture was partitioned between Et₂ O/ice-H₂ O/2N HCl (aq.) and theorganic phase separated, washed with ice-H₂ O (3×), and saturated NaClsolution, dried over NaSO₄, filtered, and evaporated.

The residue was purified by PLC [1 development petroleum ether] to give500 mg (92%) of 3-bromo-5-t-butyldimethylsilyloxybiphenyl; NMR (CDCl₃)δ: 0.14 (s, Si(CH₃)₂), 1.0 (s, SiC(CH₃)₃), 6.98 (m, Ar-H), and 7.44 (m,Ar-H).

EXAMPLE 16 ##STR36##

To a stirred solution of 11.1 g (69,4 mmole) of potassium ethylxanthatein 120 mL acetone at 0° C. under a nitrogen atmosphere was added all atonce 20 g (49.4 mmoles) of biphenyldiazonium salt from Example 11. Themixture was stirred 1.3 hours at 0° C. and 0.75 hours at ambienttemperature. The mixture was partitioned between Et₂ O/ice-H₂ O and theorganic phase was separated, washed with brine, and dried over NaSO₄/MgSO₄, filtered, and evaporated to a brown oil. The residue waspurified by silica gel chromatography to give 3.5 g of pure3-bromo-5-ethylxanthylbiphenyl; NMR (CDCl₃) δ: 1.36 (t, CH₃), 4.62 (q,OCH₂), 7.3-7.7(m, Ar-H).

EXAMPLE 17 ##STR37##

To a stirred solution of 10.79 g (30.7 mmole) of xanthate derivativefrom Example 16 in 140 mL of anhydrous THF at 0° C. under a nitrogenatmosphere was added 6.1 mL (92 mmole) of ethylene diamine and themixture stirred further for 10 minutes. After this time, 5.4 mL (86mmole) of methyl iodide was added, the ice-H₂ O bath removed, and themixture stirred 1 hour longer.

The mixture was partitioned between Et₂ O/ice-H₂ O and the organic phaseseparated, washed with brine, dried over Na₂ SO₄ /MgSO₄, filtered, andevaporated.

The residue was purified by distillation to give 5.82 (68%) of3-bromo-5-methylthiobiphenyl; NMR (CDCl₃) δ: 2.55 (s, SCH₃), 7.36-7.56(m, Ar-H); MS: m/e 280, 278 (M⁺).

EXAMPLE 18 ##STR38##

A stirred mixture of 1.19 g (5.84 mmole) of 85% m-chloroperoxybenzoicacid and 1.24 g (4.49 mmole) of 3-bromo-4'-acetylbiphenyl [preparedaccording to E. Berliner and E. A. Blommers, JACS, 73, 2479 (1951)] in15 mL 1,2-dichloroethane was refluxed under a nitrogen atmosphere for 17hours.

The cooled mixture was partitioned between Et₂ O/ice-H₂ O/5% Na₂ S₂ O₃(aq.) solution and the organic phase separated, washed with ice-H₂O/saturated NaHCO₃ (aq.) solution and then saturated NaCl solution,dried over Na₂ SO₄, filtered, and evaporated.

The residue was purified by PLC [one development CH₂ Cl₂ -petroleumether] to give 1.09 g (83%) of 3-bromo-4-acetoxy-biphenyl; NMR (CDCl₃)δ: 2.33 (s, OAc), 7.14-7.7 (m, Ar-H).

EXAMPLE 19 ##STR39##

To a stirred solution of 1.07 g (3.67 mmole) of3-bromo-4-acetoxybiphenyl in 10 mL methanol at ambient temperature undera nitrogen atmosphere was added 0.92 mL of 4.4 M sodium methoxide inmethanol solution (4 mmole). The mixture was stirred for 20 minutes andpartitioned between Et₂ O/ice-H₂ O/2N HCl (aq.) and the organic phaseseparated, washed with saturated NaCl solution, and then ice-H₂O/saturated NaHCO₃ (aq) solution, dried over Na₂ SO₄, filtered, andevaporated. The product was dried in vacuo to give 1.05 g of crude3-bromo-4'-hydroxybiphenyl which was used without further purification.

EXAMPLE 20 ##STR40##

Step (a)

To a stirred solution of 816 μL (6.2 mmole) of 90% t-butylnitrite in 15ml of DMF at 65° C. under nitrogen atmosphere was added dropwise, asolution of 905 mg (3.1 mmole) 3-bromo-3'-nitro-4'-aminobiphenyl [C.Dell'Erba, G. Garbarino, and G. Guanti, Tetrahedron, 27. 113 (1971)]in 10 mLDMF over a period of 6 minutes. The mixture was stirred further as abovefor 8 minutes.

The cooled mixture was partitioned between Et₂ O/ice-H₂ O, and theorganic phase separated, washed twice with ice-H₂ O, then with saturatedNaCl solution, dried over Na₂ SO₄, filtered, and evaporated.

The residue was purified by florisil chromatography with CH₂ Cl₂-petroleum ether solvent to give a quantitative yield of3-bromo-3'-nitrobiphenyl; NMR (CDCl₃) δ: 7.32-8.46 (m, Ar-H).

Using the analogous procedure outlined in Exs. 10, 11 and 12,3-bromo-3'-fluorobiphenyl was obtained.

EXAMPLE 21 ##STR41##

In a fashion analogous to the procedures outlined in Examples 13-15, the3-bromo-3'-amino-biphenyl from Example 20 was converted into3-bromo-3'-t-butyldimethylsiloxybiphenyl.

EXAMPLE 22 ##STR42##

Utilizing the procedures previously outlined, the diazonium salt ofExample 20 was converted to 3-bromo-3'-methylthiobiphenyl.

EXAMPLE 23 ##STR43##

3-bromo-4'-acetamidobiphenyl was prepared according to the method of C.Dell 'Erba, et al., Tetrahedron, 27, 113 (1971), and converted into thethree 3-bromo-4'-substituted biphenyl derivatives depicted aboveutilizing the previously detailed procedures.

EXAMPLE 24 ##STR44##

3-bromo-5-fluoro-4'-t-butyldimethylsilyloxy-biphenyl was prepared infour steps utilizing the procedures previously detailed.

EXAMPLE 25 ##STR45##

3-bromo-5-fluoro-4'-t-butyldimethylsilyloxymethylbiphenyl wassynthesized as outlined above employing the previously describedprocedures.

EXAMPLE 26 ##STR46##

Three 3-bromo-5-fluoro-4'-substituted biphenyl derivatives depictedabove were prepared by the standard procedures previously disclosed.

EXAMPLE 27 ##STR47##

Step(a)

To a stirred solution of sodium nitrite (4.4 g; 63.9 mmol) in 44.3 ml ofsulfuric acid in an ice-water bath was added a solution of3-amino-5-bromobiphenyl (15.0 g, 60.1 mmol) in 176.7 ml glacial aceticacid over 30 minutes. The solution was stirred an additional 10 minutes.To a stirred solution of copper(I)bromide (9.5 g, 66.3 mmol) in 78.6 mlof 48% HBr at R.T. was added the above diazonium salt solution and thereaction mixture was stirred for 45 minutes under an inert atmosphere ofnitrogen. The reaction appeared complete by TLC (petroleum ether). Thereaction was quenched by the addition of a 1.5 L 5N NaOH-ice solutionand the aqueous portion (pH 6.5) was extracted with 2.0 L ether. Theether extract was washed three times with brine and the solvent wasremoved in vacuo to provide 18.6 g of a brown oil. The crude materialwas purified by flash chromatography on silica gel eluting with hexanes.The higher R_(f) product gave 15.6 g (83.1%) of 3,5-dibromobiphenyl andthe lower R_(f) by product gave 0.7 g of 3-bromobiphenyl.

¹ H NMR (300 MHz, CDCl₃, ppm): δ 7.36-7.54 (m,5H); 7.6-7.68 (m,3H).

Step(b)

To a stirred solution of 3,5-dibromo-biphenyl (0.5 g, 1.60 mmol), in 5ml dry THF under N₂ atmosphere at -78° C., was added 0.67 ml of 2.5Mn-butyllithium (1.68 mmol). A clear yellow solution resulted. Afterstirring 5 minutes, a solution of SO₂ (g) (0.12 g) in 1.0 ml THF wasadded via syringe; TLC indicated nearly complete reaction. To thestirred reaction mixture was added2,4,6-triisopropylbenzenesulfonylhydroxylamine (0.57 g, 2.0 mmol) and itwas stirred for 15 minutes. The reaction appeared incomplete by TLC, andadditional aminating agent (45.3 mg, 0.1 mmol) was added and thereaction stirred 15 minutes. This process was repeated and then thereaction mixture was partitioned between ethyl acetate/ice/water; theorganic layer was separated and washed three times with 10 ml H₂ O, andthree times with 10 ml brine. The organic layer dried over MgSO₄,filtered and the solvent removed in vacuo, to give 1.0 g crude ofproduct. The residue was purified by plate-layer chromatography elutedwith dichloromethane-ethyl acetate (30:1) to give 300 mg (60%).

¹ H NMR (200 MHz, DMSO, ppm): δ 7.47-7.59 (m, 3H), 7.71-7.78 (m, 2H),7.95 (m, 1H), 8.08-8.13 (m, 2H)

IR: (nujol) 3370,3275 cm⁻¹.

MS: (m/e) 313,311 (M⁺).

Step(c)

A mixture of 3-bromo-5-sulfonylbiphenyl (0.11 g, 0.36 mmole), Pd(PPh₃)₄(8.4 mg, 7.3 μmol) and triphenylphosphine (1.0 mg, 3.8 μmol) in 1.33 mLtoluene was stirred and degassed with a nitrogen purge. A solution ofhexamethylditin (130.8 mg, 0.40 mmol) in 0.30 μL toluene was added viasyringe and the solution was refluxed under N₂ for 2 h. The cooledreaction mixture was partitioned between ethyl acetate/ice/water/aq.NaHCO₃. The organic layer was separated and washed three times with 10ml of cold (0° C.) 10% aq. NaHCO₃ solution and twice with 10 ml brine;dried over MgSO₄, filtered and concentrated in vacuo. The crude product,a yellow-orange oil was purified by chromatography on silica gel plates(2000μ) eluted with 30:1 CH₂ Cl₂ : EtOAc to give 95 mg (66.1%), as awhite foam.

¹ H NMR (300 MHz, CDCl₃, ppm): δ 0.38 (s, 9H), 4.96 (bs, 2H), 7.35-7.48(m, 3H), 7.55-7.59 (m, 2H), 7.85 (m, 1H), 8.0 (m, 1H), 8.06 (m, 1H).

IR: (CH₂ Cl₂) 3430, 3335 cm⁻¹.

Step(d)

A stirred mixture of the sulfonamide (25 mg, 0.08 mmol),t-butyldimethylsilyl chloride (0.60 mg, 4.0 μmol), andN-tert-butyldimethylsilyl)-N-trifluoromethylacetamide (20.7 μL, 88 μmol)in 0.5 ml MeCN was refluxed for 2 hours under N₂ atmosphere. The cooledreaction mixture was partitioned between EtOAc/ice/water/aq. NaHCO₃. Theorganic layer was separated and washed three times with 10 mL dilute aq.NaHCO₃ solution and three times with 10 mL brine; dried over MgSO₄ ;filtered and concentrated in vacuo to give 27 mg of crude product. Itwas chromatographed on a silica gel plate (1000μ) eluted with 9:1 CH₂Cl₂ : hexane to give 24 mg(70.3%) of product.

¹ H NMR (200 MHz, CDCl₃, ppm): δ 0.28 (s, 6H), 0.94 (s, 9H); 4.46 (bs,1H), 7.43-7.60 (m, 5H), 7.89 (m, 1H), 7.99 (m, 1H), 8.03 (m, 1H).

Step(e)

To a stirred solution of the silylated sulfonamide (42.7 mg, 0.1 mmol)in 0.43 ml DMF was added 4.3 mg (0.11 mmol) of a 61.1% mineral oildispersion of NaH. The mixture was stirred under N₂ at ambienttemperature for 1 hr. To the stirred mixture was added neat methyliodide(29.8 mg, 0.21 mmol) and stirred further for 3 hours; followed thereaction by TLC (1:1 hexane: dichloromethane). The reaction mixture waspartitioned between ethyl acetate/ice and water, and the organic layerseparated, washed three times with 20 mL deionized water and three timeswith 20 mL brine; then dried over MgSO₄, filtered and concentrated invacuo. The crude product (44.0 mg) was chromatographed on a silica gelplate (1000μ) eluted with 1:1 hexane: dichloromethane to give 32.0 mg(78.1%) purified product.

¹ H NMR (200 MHz, CDCl₃, ppm): δ 0.38 (s, 6H), 1.07 (s, 9H), 2.80 (s,3H), 7.44-7.62 (m, 5H), 7.92 (m, 2H), 7.97 (m, 1H).

Step(f)

To a stirred solution of3-bromo-5-N-t-butyldimethylsilyl-N-methylsulfonamidobiphenyl (32.0 mg,73.0 μmol) in 0.32 ml anhydrous THF at 0° C. under N₂ was addedsequentially 12.5 μl (0.22 mmol) glacial acetic acid and then a 1Msolution of tetrabutylammonium fluoride (80.3 μl, 80.3 μmol) in the THF.The mixture was stirred at 0° C. for 0.5 hr. The reaction mixture waspartitioned between EtOAc/ice-water, the organic layer was separated andwashed three times with saturated sodium bicarbonate solution, threetimes with 10 mL water and three times with 10 mL brine, then dried overNa₂ SO₄, filtered and the solvent removed in vacuo to give 28 mg ofcrude product. The mixture was chromatographed on a 1000μ silica gelplate eluting with 9:1 dichloromethane: hexane to give 24 mg (84%) thedesired N-methyl sulfonamide.

¹ H NMR (200 MHz, CDCl₃, ppm): δ 2.75 (d, 3H), 4.4 (bm, 1H), 7.45-7.61(m, 5H), 7.96 (m, 1H), 7.98 (m, 1H), 8.0 (m, 1H).

Using the procedures disclosed in step(c), this material was convertedinto the analogous trimethylstannyl derivative.

Step(g)

To a stirred solution of the sulfonamide (0.2 g, 641 μmol) in 2 ml DMFwas added 52.6 mg (1.34 mmol) 61.1% of a mineral oil dispersion of NaHand the reaction stirred 1 hour at room temperature until gas evolutionis complete. To the stirred mixture at 0° C. was added neat methyliodide(0.17 mL), and the solution stirred 30 minutes; TLC (1:1 CH₂ Cl₂ :hexane) indicated complete reaction. The reaction mixture waspartitioned between ethyl acetate and ice-water, and the organic extractseparated, washed three times with 50 mL brine, dried over Na₂ SO₄,filtered and concentrated in vacuo to give 250 mg of crude product. Itwas chromatographed on two 2000μ silica gel plates eluted with 1:1hexane: dichloromethane to give 201 mg(92.2%) the desired product.

¹ H NMR (200 MHz, CDCl₃, ppm): δ 2.8 (s, 6H), 7.46-7.62 (m, 5H), 7.91(m, 2H), 7.96 (m, 1H).

Using the procedure described in step(c), this biphenyl derivative wasconverted to the analogous trimethylstannyl derivative.

EXAMPLE 28 ##STR48##

Step (a)

To a stirred solution of 3-bromo-5-iodobiphenyl (5.5 g, 15.4 mmol) in 70mL dry THF at -78° C. under N₂ atmosphere was added dropwise a 2.5Msolution of n-butyllithium in hexanes (6.4 mL, 16.1 mmol) over 5minutes. The mixture was stirred 10 minutes and anhydrous DMF (2.4 mL,30.7 mmol) was quickly added. After 15 minutes the reaction was quenchedby the addition of saturated ammonium chloride solution and warmed toroom temperature. The reaction mixture was partitioned between diethylether and water, the organic extract washed with brine, dried overMgSO₄, filtered and concentrated in vacuo. The crude product (4.37 g),as a yellow oil, was chromatographed on silica gel eluted with agradient of 0-3% ethyl acetate in hexane to provide. 3.61 g. (90%) ofpurified product, as an opaque oil. ¹ H NMR (200 MHz, CDCl₃, ppm): δ7.4-8.04 (m, 8H), 10.04 (s, 1H);

IR: (CH₂ Cl₂): 1700 cm⁻¹ ;

MS: m/e 262,260 (M⁺).

EXAMPLE 29 ##STR49##

To a stirred solution of 3-bromo-5-iodobiphenyl (0.5 g, 1.4 mmol) in 5mL dry THF at -70° C. under N₂ atmosphere was added a 2.5M solution ofn-butyllithium in hexanes (.58 mL, 1.47 mmol). The mixture was stirred10 minutes, and a 0.2M solution of magnesium bromide (14 mL, 2.8 mmol)in THF was added. The reaction was warmed to -23° C. in a dry ice-CCl₄bath. After 15 minutes at -23° C., neat 2-acetylthiopyridine (178 μl,1.40 mmol) was added and the reaction was monitored by TLC. The2-acetylthiopyridine was completely consumed after 10 minutes however,starting material remained, and an additional 50 μl of2-acetylthiopyridine was added. The reaction mixture was warmed to roomtemperature and quenched with 3 mL of 1M aqueous NH₄ Cl and thenpartitioned between ethylacetate and cold water. The organic layer wasseparated and washed with cold 2N NaOH and brine, then dried over MgSO₄,filtered and concentrated in vacuo to give 486 mg of crude material. Itwas chromatographed on two 2000μ silica gel plates eluted with 9:1hexane:ethylacetate to give 202 mg (52%), as a crystalline solid.

¹ H NMR (200 MHz, CDCl₃, ppm): δ 2.64 (s, 3H), 7.4-8.1 (m, 8H);

IR (CH₂ Cl₂): 1690 cm⁻¹.

EXAMPLE 30 ##STR50##

To a dry flask charged with the bicyclic ketoester carbapenem derivative(58.4 mg, 0.168 mmol) and purged with N₂ was added 1.0 mL dry THF. Thesolution was chilled to -78° C. and diisopropylamine (25.8 μL, 0.184mmol) was added. The reaction was stirred 10 minutes and became a clearyellow solution, then trifluoromethanesulfonic anhydride (30.6 μL, 0.184mmol) was added and stirring continued at -78° C. for 15 minutes. To thereaction mixture was added neat triethylamine (25.4 μL, 184 μmol) andtrimethylsilyl trifluoromethanesulfonate (35.6 mL, 184 μmol) andcontinued stirring for 20 minutes.

The arylstannane sulfonamide (73.0 mg, 0.18 mmol), Pd₂ (dba)₃. CHCl₃(3.47 mg, 3.4 μmol) and tris (2,4,6-trimethoxyphenyl)phosphine (7.11 mg,13.5 μmol) were added all at once after the addition of 0.83 mLN-methylpyrolidinone. Finally, a solution of 1.5M zinc chloride indiethyl ether (276 μl, 0.184 mmol) was added, and the reaction mixturewas allowed to warm with the aid of a warm water bath for an additional20 minutes during which time a wine red color developed. The reactionmixture was partitioned between ethyl acetate/ice and aqueous. NaHCO₃mixture and the organic layer was separated and washed three times with10 mL cold dilute NaHCO₃ and three times with 10 ml brine; dried overMgSO₄, filtered, and concentrated in vacuo. Chromatographed crudeproduct on one 1000μ silica gel plate eluted with 2:3 hexane:ethylacetate to give 70.2 mg (61.0%) of product.

¹ H NMR (300 MHz, CDCl₃, ppm): δ 0.12 (s, 9H), 1.25 (d, 3H), 3.19-3.41(m 3H), 4.21-4.32 (m, 2H) 5.15 (d, 1H), 5.25 (d, 1H), 7.24-8.11 (m,12H).

EXAMPLE 31 ##STR51##

To a stirred solution of the silyl ether (67.0 mg, 0.107 mmol) in 1 mLdry THF at 0° C. was added glacial acetic acid (18.3 μl 0.321 mmol) anda solution of 1M tetrabutylammoniumfluoride in THF (107 μl, 0.107 mmol).The reaction mixture was stirred 10 minutes and then partitioned betweenEtOAc/ice/water/dilute aq. NaHCO₃. The organic layer was separated andwashed three times with 10 mL saturated NaHCO₃ solution and three timeswith 10 mL brine, then dried over MgSO₄, filtered and concentrated invacuo. The crude product (55.0 mg), a yellow foam, was chromatographedon a 1000μ silica gel plate eluting with 7:3 hexane:ethyl acetate togive the purified product 35.0 mg (59.2%).

¹ H NMR (300 MHz, d₆ -Me₂ CO, pp,)δ: 1.32 (d, 3H), 3.38 (dd, 1H), 3.52(dd, 1H), 3.7 (dd, 1H), 4.2 (m, 1H), 4.45 (m, 1H), 5.35 (ABq, 2H), 6.75(bs, 2H) 7.4-7.7 (m, 5H), 7.94 (m, 1H), 8.15 (m, 2H);

IR (CH₂ Cl₂): 1775, 1725 cm⁻¹ ;

UV (dioxane, λmax): 310 nm (sh), 259 nm.

EXAMPLE 32 ##STR52##

A mixture in 0.5 mL dry THF of p-nitrobenzyl ester (35.0 mg, 63.5 μmol),3.5 mg 10% Pd/C, and NaHCO₃ (6.0 mg) was hydrogenated at 50 psi andambient temperature for 15 minutes. After this time an additional 3.5 mg10% Pd/C was added and the hydrogenation continued for 30 minutes at 50psi. The reaction mixture was filtered through a celite pad to give aclear filtrate, which was concentrated in vacuo. The solid residue wasdissolved in deionized H₂ O and chromatographed on a 1000μ reverse phasesilica gel plate eluted with 5:1 water: acetonitrile in a chilleddeveloping chamber. The product 14.5 mg (50.5%) was isolated as a whitefluffy solid, after lyophilization.

¹ H NMR (300 MHz, D₂ O, ppm) δ: 1.24 (d, 3H), 3.18 (m, 1H), 3.56 (m,1H), 3.64 (m, 1H), 4.38 (m, 2H), 7.5-7.82 (m, 5H), 7.87 (m, 2H), 8.08(bs, 1H);

IR (nujol): 1750, 1595 cm⁻¹ ;

UV (H₂ O, λmax): 303, 254 nm.

EXAMPLE 33 ##STR53##

To a stirred solution of the carbapenem derivative (60 mg, 0.103 mmol)in 0.6 mL dry acetonitrile at 0° C. under N₂ atmosphere was added neatN-methylimidazole (17.2 μl, 0.216 mmol) and trifluoromethanesulfonicanhydride (18.2 μl, 0.108 mmol). The progress of the reaction wasfollowed by TLC. After 15 minutes, the TLC indicated the completedisappearance of starting material. The reaction mixture wasconcentrated in vacuo. The 200 MHz NMR indicated a mixture of vinylsulfone and the imidazolium adduct. The crude product was dissolved indichloromethane, transferred into a 15 ml centrifuge tube, concentratedto a 1.0 mL volume and the imidazolium adduct precipitated by theaddition of diethyl ether. After centriguging the ether was decantedoff, and evaporated to yield 32 mg (55%) of the vinyl sulfone product asa white foam.

¹ H NMR (200 MHz, CDCl₃, ppm) δ: 1.52 (d, 3H), 3.31-3.39 (m, 2H),3.46-3.51 (dd, 1H), 4.31-4.41 (dt, 1H), 4.65-4.74 (m, 4H), 5.16-5.44 (m,5H), 5.79-6.04 (m, 2H), 6.1 (d, 1H), 6.52 (d, 1H), 6.66 (dd, 1H),7.4-7.63 (m, 5H), 7.83-7.87 (m, 2H), 8.06 (m, 1H).

EXAMPLE 34 ##STR54##

To a stirred solution of 2-(5'-methylthio-3'-biphenyl)carbapenem (41.1mg, 79.2 μmol) in 1 mL dichloromethane at 0° C. under a N₂ atmospherewas added 0.5 M aqueous NaHCO₃ (0.5 mL) and MCPBA (19.1 mg, 0.11 mmol).The reaction was stirred 25 minutes at 0° C.; at 10 minutes the TLCindicated the complete consumption of the methyl sulfide and thepresence of two new spots. The reaction was quenched with 0.5 M aqueousNa₂ S₂ O₃ solution and partitioned between EtOAc/ice/water. The organicphase was separated and washed with brine, dried over Na₂ SO₄, filteredand concentrated in vacuo to give 46.2 mg of crude product mixture, aclear film. It was chromatographed on a 1000μ silica gel plate elutingwith 15% EtOAc in dichloromethane to give 9.3 (21.3%) of sulfone, as themore mobile component; and 25.8 mg (60.9%) of sulfoxide, as the lessmobile component.

Sulfoxide:

¹ H NMR: (300 MHz, CDCl₃, ppm)δ: 1.48 (d, 3H), 2.77 (s, 3H), 3.25-3.36(m, 2H), 3.44 (dd, 1H), 4.33 (td, 1H), 4.59-4.72 (m, 4H), 5.13-5.39 (m,5H), 5.78-5.97 (m, 2H), 7.24-7.79 (m, 8H);

IR: (CH₂ Cl₂) 1772, 1745, 1720 cm⁻¹ ;

UV: (dioxane) λmax 314,258 nm.

Sulfone:

¹ H NMR: (300 MHz, CDCl₃, ppm)δ; 1.48 (d, 3H), 3.09 (s, 3H), 3.26-3.36(m, 2H), 3.45 (dd, 1H), 4.33 (td, 1H), 4.61-4.71 (m, 4H), 5.14-5.39 (m,5H), 5.79-5.92 (m, 2H), 7.24-8.09 (m, 8H);

IR: (CH₂ Cl₂) 1775, 1745, 1722 cm⁻¹ ;

UV: (dioxane) λmax 312,257 nm.

EXAMPLE 35 ##STR55##

Step (a)

To a stirred solution of 65.3 mg (0.13 mmole) of carbapenem biphenylcarbinol derivative in 1.6 mL sieve dried CH₂ Cl₂ at ambient temperaturewas added sequentially 17 mg of powdered 3 Å sieves and 27 mg (0.23mmole) of N-methylmorpholine-N-oxide. The yellow solution was stirredfor 5 minutes and then 9.1 mg (0.26 mmole) of tetrapropylammoniumperruthenate was added. The resulting mixture was stirred 5 minutes andthen quickly filtered through a layer of silica gel with CH₂ Cl₂ -EtOAc(1:1) solvent. The filtrate was rotoevaporated and dried in vacuo togive 51.9 mg (80%) of oxidized product; NMR (CDCl₃) δ: 1.5 (d, CH₃),3.34 (m, 2H-1). 3.46 (dd, 1H-6), 4.34 (td, 1H-5), 4.34 (m, 2--OCH₂CH═CH₂), 5.24 (m, 1H-8 and 2--CH═CH₂), 5.88 (m, 2--CH═CH₂), 7.46 (m,3Ar-H), 7.6 (d, 2Ar-H), 7.82 (s, 1Ar-H), 7.84 (s, 1Ar-H), 8.05 (s,1Ar-H), and 10.1 (s, CHO).

EXAMPLE 36 ##STR56##

To a stirred solution of 51.9 mg (0.1 mmole) of carbapenem biphenylcarboxaldehyde derivative from Example 35 in 0.7 mL absolute ethanol and0.7 mL pyridine at 0° C. under a nitrogen atmosphere was added 7.2 mg(0.1 mmole) of neat hydroxylamine hydrochloride. The mixture was stirredat 0° C. for 5 minutes and then partitioned between EtOAc/ice/saturatedNH₄ Cl (aq.) solution and the organic phase separated. It was washedsuccessively with ice/saturated NaHCO₃ (aq.) solution, H₂ O, and brine,then dried over Na₂ SO₄, filtered, and evaporated.

The crude oxime was immediately employed in the next transformation butmaybe purified by PLC to give pure material; IR (CH₂ Cl₂): 3560, 1780,1745, and 1720 cm⁻¹ ; NMR (CDCl₃) δ: 1.52 (d, CH₃), 1.6 (bs, OH), 3.32(m, 2H-1), 3.46 (dd, 1H-6), 4.34 (dt, 1H-5), 4.68 (m, 2--OCH₂ CH═CH₂),5.24 (m, 1H-8 and 2--CH═CH₂), 5.84 (m, 2--CH═CH₂), 7.36-7.78 (m, Ar-H),and 8.2 (s, CH═NO).

EXAMPLE 37 ##STR57##

To a stirred solution of 53.1 mg (0.1 mmole) of crude oxime from Example36 in 1.6 mL of sieve dried CH₂ Cl₂ at -78° C. under a nitrogenatmosphere was added sequentially 21.9 mg (0.22 mmole) of neattriethylamine and 29.1 mg (0.1 mmole) of neat triflic anhydride. Afterstirring 15 minutes at -78° C., an additional 13.4 mg (0.05 mmole) oftriflic anhydride was added and the mixture stirred further for 15minutes.

The mixture was partitioned between EtOAc/ice/saturated NH₄ Cl (aq.)solution and the organic phase was separated, washed with saturatedNaHCO₃ (aq.) solution/ice and then brine, dried over Na₂ SO₄, filtered,and evaporated.

The residue was purified by PLC [one development 5% EtOAc in CH₂ Cl₂ ]to give 24.3 mg (47%) of biphenylnitrile carbapenem derivative; IR (CH₂Cl₂) 2235, 1780, 1745, and 1720 cm⁻¹ ; NMR (CDCl₃) δ: 1.5 (d, CH₃), 3.29(m, 2H-1), 3.46 (dd, 1H-6), 4.34 (td, 1H-5), 4.66 (m, 2--OCH₂ CH═CH₂),5.26 (m, 1H-8 and 2--CH═CH₂), 5.88 (m, 2CH═₂), 7.38-7.83 (m, Ar-H).

EXAMPLE 38 ##STR58##

To a stirred solution of 500 mg (0.65 mmole) ofbiphenylcarbinolazetidnonylphosphorane derivative in 10 mL acetone at 0°C. was added slowly 0.75 mL (2.0 mmole) of 2.67 M Jones reagent. Themixture was stirred 15 minutes at ice-H₂ O bath temperatures and 3 mL ofsaturated NaHSO₃ (aq.) solution added. The reaction solution wasdecanted and partitioned between EtOAc/ice/0.1M pH 7 phosphate buffer.The organic phase was separated, dried over Na₂ SO₄, filtered,evaporated, and dried in vacuo to give 287 mg (57%) of crude aciddervivative; IR (CH₂ Cl₂) 1743, 1690, and 1605 cm⁻¹.

To a stirred solution of 254 mg (0.32 mmole) of crude acid in 4 mL ofDMF at ambient temperature was added 62 mg (0.48 mmole) ofdiisopropylethylamine and 58 mg (0.48 mmole) of allyl bromide. Theresulting solution was stirred overnight at room temperature.

The reaction mixture was concentrated in vacuo and the concentratepartitioned between EtOAc and cold 1N HCl, and the organic phaseseparated, dried over Na₂ SO₄, filtered, and evaporated.

The residue was purified by PLC [one development CH₂ Cl₂ -EtOAc (9:1)]to give (64%) of foamy ester product; IR (CH₂ Cl₂) 1743, 1725 (sh),1690, and 1610 cm⁻¹.

EXAMPLE 39 ##STR59##

Step (a)

To a stirred solution of 140 mg (0.18 mmole) of carboxylic acidderivative, prepared according to Example 38, in 4 mL THF at roomtemperature was added 45 mg (0.34 mmole) of neat 1-hydroxybenzotriazoleand 44 mg (0.23 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride were added, and the mixture stirred 0.75 hours. After thistime 2 mL of cold, saturated NH₃ in THF solution was added and themixture stirred for 1.0 hour. The reaction mixture was concentrated andpurified by column chromatography on silica gel to give the amideproduct;

IR (CH₂ Cl₂) 1743, 1680, and 1610 cm⁻¹.

EXAMPLE 40

Utilizing the procedure outlined in Example 39 and substituting MeOH forNH₃ /THF, the corresponding methyl ester was prepared.

EXAMPLE 41 ##STR60##

To a stirred solution of 209.7 mg (0.4 mmol) of carbapenem derivative41A in 3 mL of sieve dried methylene chloride at 0° C. under a nitrogenatmosphere was added sequentially 13.1 mg (0.165 mmol) of pyridine andthen 117 mg (0.62 mmol) of trichloroacetylisocyanate. The resultingmixture was stirred at 0° C. for 40 minutes.

The reaction mixture was partitioned between ethylacetate, ice-H₂ O, and2N hydrochloric acid. The organic phase was separated, washed withsaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate, filtered, evaporated, and dried in vacuo to give 313 mg ofcrude intermediate.

The intermediate was dissolved in 5 mL methanol cooled to 0° C. in anice-H₂ O bath, slurried with sufficient EM-60 silica gel and stirredfurther for 1 hour, and then aged overnight under refrigeration. Thereaction mixture was filtered, washed with ether and the filtrateevaporated.

Purification by plate layer chromatography on two 1000 silica gel platesdeveloped with methylene chloride-ether (6:1) provided 157.4 mg (69%) of41B:

IR (CH₂ Cl₂): 3535, 3430, 1780, 1750, 1720 cm⁻¹ ;

¹ H NMR (200 MHZ, CDCl₃, ppm): δ 1.53 (d, 3H), 3.16-3.40 (m, 2H), 3.44(dd, 1H), 4.32 (dt, 1H), 4.66 (m, 4H), 5.06 (bs, 2H), 5.1-5.44 (m, 5H),5.74-6.04 (m, 2H), 6.98-7.58, (m, 7H),

UV (dioxane, λmax: 310, 277 nm.

EXAMPLE 42 ##STR61##

To a stirred solution of 45.9 mg (0.08 mmol) of carbapenem derivative42A in 2 mL sieve dried acetonitrile at 0° C. under a nitrogenatmosphere was added 17.7 μL (0.16 mmol) of triethylamine and then 8.4μL (0.12 mmol) of acetyl chloride. The reaction mixture was stirred 25min. at 0° C. and then partitioned between EtOAc/ice-H₂ O. The organicphase was separated, washed with cold, saturated NaHCO₃ (aq) solution,then with saturated sodium chloride solution, dried over anhydrous Na₂SO₄, filtered, evaporated, and dried in vacuo to give a quantitativeyield of acetoxyl derivative 42B;

IR (CH₂ Cl₂): 1780, 1745, 1722 cm⁻¹ ;

¹ H NMR (300 MHZ, CDCl₃, ppm): δ 1.48 (d, 3H), 2.3 (s, 3H), 3.18-3.36(m, 2H), 3.41 (dd, 1H), 4.28 (td, 1H), 4.58-4.76 (m, 4H), 5.1-5.4 (m,5H), 5.74-5.95 (m, 2H), 7.06-7.54 (m, 8H).

UV (dioxane, λ_(max) : 320, 252 nm.

EXAMPLE 43 ##STR62##

A mixture of 12.6 mg (0.1 mmole) isonicotinic acid and 20.1 mg (0.12mmole) of carbonyl diimidazole in 3 mL sieve dried acetonitrile wasstirred ar 0° C. under a nitrogen atmosphere for 10 minutes and then atambient temperature for 0.75 hours. After this time, 60 mg (0.1 mmole)of neat hydroxybiphenyl carbapenem derivative was added and theresulting mixture stirred further for 17 hours.

The mixture was partitioned between EtOAc and ice-H₂ O and the organicphase separated, washed with saturated NaCl solution, dried over Na₂SO₄, filtered, and evaporated.

The residue was purified by PLC [two developments CH₂ Cl₂ -EtOAc (4:1)]to give 17.1 mg (24%) of product; NMR (CDCl₃) δ: 1.5 (d, CH₃), 3.25 (m,2H-1), 3.44 (dd, 1H-6), 4.32 (td, 1H-5), 4.68 (m, 20CH₂ CH═CH₂), 5.28(m, 2CH═CH₂ and 1H-8), 5.9 (m, 2CH═CH₂), 7.28-7.68 (m, 8ArH), 8.04 (d,2PyH), and 8.88 (d, 2PyH); IR(CH₂ Cl₂): 1780, 1745, and 1725 cm⁻¹ ; UV:λ_(max) ^(dioxane) 255 nm, 300 nm (sh).

EXAMPLE 44 ##STR63##

To a stirred solution of 47.3 mg (0.9 mmole) of alcohol 4A, prepared inExample 4, in 1 mL sieve dried CH₂ Cl₂ at 0° C. under a nitrogenatmosphere was added sequentially 14.3 mg (0.14 mmole) of triethylamineand then 14 mg (0.12 mmole) of mesyl chloride. The mixture was stirredat 0° C. for 20 minutes and was then partitioned between EtOAc/ice-H₂O/2N HCl and the organic phase was separated, washed with saturatedsodium chloride solution, dried over sodium sulfate, filtered, andevaporated to give 56.6 mg of crude mesylate intermediate.

The crude mesylate was dissolved in 1 mL acetone and stirred with 28.2mg (0.19 mmole) of sodium iodide in the cold for a few minutes and thenfurther, with the ice-H₂ O bath removed, for 1.0 hour. After this timethe mixture was partitioned between EtOAc/ice-H₂ O/5% aqueous sodiumthiosulfate solution, and the organic phase was separated, washed withbrine, dried over anhydrous sodium sulfate, filtered, and evaporated togive 53.7 mg of crude product.

Purification by PLC, [1 development hexane-EtOAc (2:1)] gave 28.3 mg(49%) of oily iodide 44A; IR(CH₂ Cl₂): 1785, 1750, 1725 cm⁻¹ ;NMR(CDCl₃) δ: 1.54 (d, J=6.4 Hz, CH₃), 3.26 (dd, 1-H-1), 3.36 (dd,1-H-1), 3.46 (dd, 1-H-6), 4.32 (dt, 1-H-5), 4.55 (s, CH₂ I), 7.3-7.62(m, Ar-H); UV: λ_(max) ^(dioxane) 284 nm.

EXAMPLE 45 ##STR64##

To a stirred solution of 40.6 mg (0.07 mmole)iodomethylbiphenylcarbapenem derivative from Example 44 in 1.5 mLacetonitrile at -20° C. under a nitrogen atmosphere was added 140 μL(0.07 mmole) of a freshly prepared stock solution of sodium2-N-methylimidazolemercaptide in DMF which was prepared by theinteraction of 250 mg (2.19 mmole) of N-methyl-2-mercaptoimidazole andsodium hydride in 5.5 mL of sieve dried DMF at 0° C. for 2 hours. Theresulting mixture was stirred further at -20° C. for 15 minutes.

The mixture was partitioned between EtOAc/ice-H₂ O and the organic phaseseparated, washed with brine, dried over Na₂ SO₄, filtered, evaporated,and dried in vacuo to give 34.9 mg (88%) of product: IR (CH₂ Cl₂) 1780,1745, and 1720 cm⁻¹ ; 1.5 (d, CH₃), 3.3 (m, 2H-1), 3.32 (s, N--CH₃),4.22 (s, --SCH₂), 4.31 (td, 1H-5), 4.68 (m, 2--OCH₂ CH═CH₂), 5.26 (m,1H-8 and 2--CH═CH₂), 5.88 (m, 2CH═CH₂), 6.88 (bs, 1-Im-H), and 7.1-7.6(m, ArH and 1Im-H); UV: λ_(max) ^(dioxane) 278 nm, 315 nm (sh).

EXAMPLES 46-91

Employing the procedures described above, additional compounds of thepresent invention were prepared which are described in the table below.

    __________________________________________________________________________     ##STR65##                                                                              R.sup.a                                                             EX #                                                                              R.sup.'                                                                          R  5         3'    4'       5'                                                                              M λ .sub.max.sup.H.sbsp.2.sup.                                           O(nm)                                  __________________________________________________________________________    46  OH H  H         H     H        H K 299,252                                    OH H  F         H     H        H K 300,251                                    OH H  OCH.sub.3 H     H        H K 302,253                                    OH H  OH        H     H        H Na                                                                              302,251                                50  OH H  SCH.sub.3 H     H        H Na                                                                              303,254                                    OH H  S(O)CH.sub.3                                                                            H     H        H K 302,253                                    OH H  SO.sub.2 CH.sub.3                                                                       H     H        H Na                                                                              306,256                                    OH H  CN        H     H        H Na                                                                              304,254                                    OH H  CO.sub.2 Na                                                                             H     H        H Na                                                                              300                                    55  OH H  CONH.sub.2                                                                              H     H        H Na                                                                              300,255                                    OH H  CO.sub.2 CH.sub.3                                                                       H     H        H Na                                                                              300                                        OH H  OCOCH.sub.3                                                                             H     H        H Na                                                                              300,253                                    OH H  H         OH    H        H Na                                                                              290,251                                    OH H  H         F     H        H Na                                                                              300,250                                60  OH H  CH.sub.2 OH                                                                             H     H        H Na                                                                              300                                        OH H  CHO       H     H        H Na                                                                              300                                        OH H  SCH.sub.2 CH.sub.2 OH                                                                   H     H        H Na                                                                              302,257                                    OH H  SO.sub.2 CH.sub.2 CH.sub.2 OH                                                           H     H        H Na                                                                              304,254                                    OH H  S(O)CH.sub.2 CH.sub.2 OH                                                                H     H        H Na                                                                              304,254                                65  OH H  SO.sub.2 NH.sub.2                                                                       H     H        H Na                                                                              304,254                                    OH H  SO.sub.2 NHCH.sub.3                                                                     H     H        H Na                                                                              305                                        OH H  SO.sub.2 N(CH.sub.3).sub.2                                                              H     H        H Na                                                                              304,254                                    OH H                                                                                 ##STR66##                                                                              H     H        H Na                                                                              305                                        OH H  COCH.sub.3                                                                              H     H        H Na                                                                              300,238                                70  OH H  CONHCH.sub.3                                                                            H     H        H Na                                                                              300,250                                    OH H  CON(CH.sub.3).sub.2                                                                     H     H        H Na                                                                              302,252                                    OH H  Br        H     H        H Na                                                                              300,255                                    OH H  SO.sub.2 CHCH.sub.2                                                                     H     H        H Na                                                                              305,256                                    OH H  H         OCONH.sub.2                                                                         H        H Na                                                                              297,252                                75  OH H  H         H     OH       H Na                                                                              300,265                                    OH H  H         H     CH.sub.2 OH                                                                            H K 296,257                                    OH H  F         H     CH.sub.2 OH                                                                            H Na                                                                              299                                        OH H  F         H     OCOCH.sub.3                                                                            H Na                                                                              300,254                                    OH H  F         H     OH       H Na                                                                              300sh,265                              80  OH H  F         H     OCONH.sub.2                                                                            H Na                                                                              300,256                                    OH H  H         H     CN       H Na                                                                              274                                        OH H  H         H     CHCHCONH.sub.2                                                                         H K 308                                                              (trans)                                                 OH H  H         H     CHCHCN   H K 309                                                              (trans)                                                 OH H  H         H     SCH.sub.3                                                                              H Na                                                                              284                                    85  OH H  H         H     SOCH.sub.3                                                                             H Na                                                                              300,268                                    OH H  H         H     SO.sub.2 CH.sub.3                                                                      H Na                                                                              300,268                                    F  H  H         H     CH.sub.2 OH                                                                            H K 298                                        OH H  H         H     CH.sub.2 SCH.sub.3                                                                     H K 302,263                                    OH βMe                                                                         H         H     CH.sub.2 OH                                                                            H K 295                                    90  OH H  H         H     NMe-imidazole-                                                                         H Na                                                                              269                                                              2-thiomethyl                                        91  OH βMe                                                                         H         H     H        H K 300                                    __________________________________________________________________________

EXAMPLES 92-118

Following the procedures described above, further examples of compoundsof the present invention may be prepared, as set out in the table below.

    __________________________________________________________________________     ##STR67##                                                                              R.sup.a                                                             EX #                                                                              R' R  5          3'   4'       5' M                                       __________________________________________________________________________     92 F  βMe                                                                         CN         H    SOCH.sub.3                                                                             H  Na                                          F  H  OH         H    SOCH.sub.3                                                                             H  Na                                          OH βMe                                                                         F          H    SO.sub.2 NH.sub.2                                                                      H  Na                                       95 OH H  H          H    OH       OH Na                                          OH H  F          H    OH       OH Na                                          OH H  CONH.sub.2 OH   OH       H  Na                                          OH H  SO.sub.3 Na                                                                              H    H        H  Na                                          OH H  PO.sub.3 Na                                                                              H    H        H  Na                                      100 OH H  H          SO.sub.2 NH.sub.2                                                                  H        H  Na                                          OH H  CF.sub.3   H    H        H  Na                                          OH H  SCF.sub.3  H    H        H  Na                                          OH H  SCN        H    H        H  Na                                          OH H  SO.sub.2 CH.sub.2 CH.sub.2 CONH.sub.2                                                    H    H        H  Na                                      105 HO H  CONHCH.sub.2 CONH.sub.2                                                                  H    H        H  Na                                          HO H  COCF.sub.3 H    H        H  Na                                          HO H  COCH.sub.2 CONH.sub.2                                                                    H    H        H  Na                                          HO H  OCH.sub.2 CH.sub.2 OH                                                                    H    H        H  Na                                          HO H  H          H    OCH.sub.2 CH.sub.2 OH                                                                  H  Na                                      110 HO H  H          H    SCH.sub.2 CH.sub.2 OH                                                                  H  Na                                          HO H  H          H    SO.sub.2 CH.sub.2 CH.sub.2 OH                                                          H  Na                                          HO H  H          H    S(O)CH.sub.2 CH.sub.2 OH                                                               H  Na                                          HO H  CH.sub.2 CONH.sub.2                                                                      H    H        H  Na                                          HO H  SCH.sub.2 CONH.sub.2                                                                     H    H        H  Na                                      115 HO H  SCH.sub.2 CN                                                                             H    H        H  Na                                          HO H  PO.sub.2 NH.sub.2                                                                        H    H        H  Na                                          HO H  SCH.sub.2 CH.sub.2 CN                                                                    H    H        H  Na                                      118 HO H  SCH.sub.2 CH.sub.2 F                                                                     H    H        H  Na                                      __________________________________________________________________________

What is claimed is:
 1. A compound of the formula: ##STR68## wherein: Ris H or CH₃ ;R¹ and R² are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂CH--, HOCH₂ --, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂CHCH(OH)--, F₃ CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;R^(a) are independently selected from the group consisting of hydrogenand the radicals set out below:(a) a trifluoromethyl group: --CF₃ ; (b)a halogen atom: --Br, --Cl, --F, or --I; (c) C₁ -C₄ alkoxy radical:--OC₁₋₄ alkyl, wherein the alkyl is optionally mono-substituted byR^(q), where R^(q) is a member selected from the group consisting of--OH, --OCH₃, --CN, --C(O)NH₂, --OC(O)NH₂, CHO, --OC(O)N(CH₃)₂, --SO₂NH₂, --SO₂ N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F, --CF₃, --COOM^(a) (whereM^(a) is hydrogen, alkali metal, methyl or phenyl), tetrazolyl (wherethe point of attachment is the carbon atom of the tetrazole ring and oneof the nitrogen atoms is mono-substituted by M^(a) as defined above) and--SO₃ M^(b) (where M^(b) is hydrogen or an alkali metal);(d) a hydroxygroup: --OH; (e) a carbonyloxy radical: --O(C═O)R^(s), where R^(s) isC₁₋₄ alkyl or phenyl, each of which is optionally mono-substituted byR^(q) as defined above;(f) a carbamoloxy radical: --O(C═O)N(R^(y))R^(z)where R^(y) and R^(z) are independently H, C₁₋₄ alkyl (optionallymono-substituted by R^(q) as defined above), together a 3- to 5-memberedalkylidene radical to form a ring (optionally substituted with R^(q) asdefined above) or together a 2- to 4-membered alkylidene radical,interrupted by --O--, --S--, --S(O)-- or --S(O)₂ --, to form a ring(where the ring is optionally mono-substituted with R_(q) as definedabove);(g) a sulfur radical: --S(O)_(n) --R^(s) where n=0-2, and R^(s)is defined above; (h) a sulfamoyl group: --SO₂ N(R^(y))R^(z) where R^(y)and R^(z) are as defined above; (i) azido: N₃ (j) a formamido group:--N(R^(t))(C═O)H, where R^(t) is is H or C₁₋₄ alkyl, and the alkylthereof is optionally mono-substituted by R^(q) as defined above;(k) a(C₁ -C₄ alkyl)carbonylamino radical: --N(R^(t))(C═O)C₁₋₄ alkyl, whereR^(t) is as defined above, and the alkyl group is also optionallymono-substituted by R^(q) as defined above; (l) a (C₁ -C₄ alkoxy)carbonylamino radical: --N(R^(t))(C═O)OC₁₋₄ alkyl, where R^(t) is asdefined above, and the alkyl group is also optionally mono-substitutedby R^(q) as defined above; (m) a ureido group:--N(R^(t))(C═O)N(R^(y))R^(z) where R^(t), R^(y) and R^(z) are as definedabove; (n) a sulfonamido group: --N(R^(t))SO₂ R^(S), where R^(s) andR^(t) are as defined above; (o) a cyano group: --CN; (p) a formyl oracetalized formyl radical: --(C═O)H or --CH(OCH₃)₂ ; (q) (C₁ -C₄alkyl)carbonyl radical wherein the carbonyl is acetalized: --C(OCH₃)₂C₁₋₄ alkyl, where the alkyl is optionally mono-substituted by R^(q) asdefined above; (r) carbonyl radical: --(C═O)R^(s), where R^(s) is asdefined above; (s) a hydroximinomethyl radical in which the oxygen orcarbon atom is optionally substituted by a C₁ -C₄ alkyl group:--(C═NOR^(z))R^(y) where R^(y) and R^(z) are as defined above, exceptthey may not be joined together to form a ring; (t) a (C₁ -C₄alkoxy)carbonyl radical: --(C═O)OC₁₋₄ alkyl, where the alkyl isoptionally mono-substituted by R^(q) as defined above; (u) a carbamoylradical: --(C═O)N(R^(y))R^(z) where R^(y) and R^(z) are as definedabove; (v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical inwhich the nitrogen atom may be additionally substituted by a C₁ -C₄alkyl group: --(C═O)--N(OR^(y))R^(z) where R^(y) and R^(z) are asdefined above, except they may not be joined together to form a ring;(w) a thiocarbamoyl group: --(C═S)N(R^(y))(R^(z)) where R^(y) and R^(z)are as defined above; (x) carboxyl: --COOM^(b), where M^(b) above; (y)thiocyanate: --SCN; (z) trifluoromethylthio: --SCF₃ ; (aa) tetrazolyl,where the point of attachment is the carbon atom of the tetrazole ringand one of the nitrogen atoms is mono-substituted by hydrogen, an alkalimetal or a C₁ -C₄ alkyl optionally substituted by R^(q) as definedabove; (ab) an anionic function selected from the group consisting of:phosphono [P═O(OM^(b))₂ ]; alkylphosphono {P═O(OM^(b))--[O(C₁ -C₄alkyl)]}; alkylphosphinyl [P═O(OM^(b))--(C₁ -C₄ alkyl)]; phosphoramido[P═O(OM^(b))N(R^(y))R^(z) and P═O(OM^(b))NHR^(x) ]; sulfino (SO₂ M^(b));sulfo (SO₃ M^(b)); acylsulfonamides selected from the structuresCONM^(b) SO₂ R^(x), CONM^(b) SO₂ N(R^(y))R^(z), SO₂ NM^(b)CON(R^(y))R^(z) ; and SO₂ NM^(b) CN, where R^(x) is phenyl orheteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, in which a carbon atom is the point ofattachment, in which one of the carbon atoms has been replaced by anitrogen atom, in which one additional carbon atom is optionallyreplaced by a heteroatom selected from O or S, and in which from 1 to 2additional carbon atoms are optionally replaced by a nitrogenheteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), as defined above; M^(b) is as defined above;and R^(y) and R^(z) are as defined above;(ac) C₅ -C₇ cycloalkyl group inwhich one of the carbon atoms in the ring is replaced by a heteroatomselected from O, S, NH or N(C₁ -C₄ alkyl) and in which one additionalcarbon atom may be replaced by NH or N(C₁ -C₄ alkyl), and in which atleast one carbon atom adjacent to each nitrogen heteroatom has both ofits attached hydrogen atoms replaced by one oxygen thus forming acarbonyl moiety and there are one or two carbonyl moieties present inthe ring; (ad) C₂ -C₄ alkenyl radical, optionally mono-substituted byone of the substituents (a) to (ac) above and phenyl which is optionallysubstituted by R^(q) as defined above; (ae) C₂ -C₄ alkynyl radical,optionally mono-substituted by one of the substituents (a) to (ac)above; (af) C₁ -C₄ alkyl radical; (ag) C₁ -C₄ alkyl mono-substituted byone of the substituents (a)-(ac) above; (ah) a 2-oxazolidinonyl moietyin which the point of attachment is the nitrogen atom of theoxazolidinone ring, the ring oxygen atom is optionally replaced by aheteroatom selected from --S-- and >NR^(t) (where R^(t) is as definedabove) and one of the saturated carbon atoms of the oxazolidinone ringis optionally mono-substituted by one of the substituents (a) to (ag)above; M is selected from:(i) hydrogen; (ii) a pharmaceuticallyacceptable esterifying group or removable carboxyl protecting group; or(iii) an alkali metal or other pharmaceutically acceptable cation. 2.The compound of claim 1 wherein R and R¹ are hydrogen.
 3. The compoundof claim 1 wherein R and R¹ are hydrogen and R² is (R)--CH₃ CH(OH)-- or(R)--CH₃ CH(F)--.
 4. The compound of claim 3 wherein R^(a) in the5-position is other than hydrogen.
 5. The compound of claim 3 whereinR^(a) is selected from the group consisting of C₁₋₄ alkylmono-substituted with hydroxy, formyl, carboxy, carbamoyl, and oximino.6. The compound of claim 3 wherein R^(a) is selected from the groupconsisting of:

    ______________________________________                                        OCH.sub.3,        CHNOCH.sub.2 CO.sub.2 H,                                    OCH.sub.2 CO.sub.2 Na,                                                                          CHNOCMe.sub.2 CO.sub.2 H,                                   OCH.sub.2 CH.sub.2 OH,                                                                          CHNOCMe.sub.2 CO.sub.2 Me,                                  CF.sub.3,         CO.sub.2 CH.sub.2 CH.sub.2 OH,                              F,                CONH.sub.2,                                                 Cl,               CONHCH.sub.3,                                               Br,               CON(CH.sub.3).sub.2,                                        I,                CONHCH.sub.2 CN,                                            OH,               CONHCH.sub.2 CONH.sub.2,                                    OCOCH.sub.3,      CONHCH.sub.2 CO.sub.2 H,                                    OCONH.sub.2,      CONHOH,                                                     SCH.sub.3,        CONHOCH.sub.3,                                              SOCH.sub.3,                                                                   tetrazolyl,                                                                   SO.sub.2 CH.sub.3,                                                                              CO.sub.2 Na,                                                SCH.sub.2 CH.sub.2 OH,                                                                          SCF.sub.3,                                                  SOCH.sub.2 CH.sub.2 OH,                                                                         PO.sub.3 NaH,                                               SO.sub.2 CH.sub.2 CH.sub.2 OH,                                                                  CONHSO.sub.2 Ph,                                            SO.sub.2 NH.sub.2,                                                                              CONHSO.sub.2 NH.sub.2,                                      SO.sub.2 N(CH.sub.3).sub.2,                                                                     SO.sub.3 Na,                                                NHCHO,            SO.sub.2 NHCN,                                              NHCOCH.sub.3,     SO.sub.2 NHCONH.sub.2,                                      NHCO.sub. 2 CH.sub.3,                                                                           CHCHCN,                                                     NHSO.sub.2 CH.sub.3,                                                                            CHCHCONH.sub.2,                                             CN,               CHCHCO.sub.2 Na,                                            CHO,              CCCONH.sub.2,                                               COCH.sub.3,       CCCN,                                                       COCH.sub.2 OH,    CH.sub.2 OH,                                                CHNOH,            CH.sub.2 N.sub.3,                                           CHNOCH.sub.3,     CH.sub.2 CO.sub.2 Na,                                       COCF.sub.3,       CH.sup.t CHCN,                                              COCH.sub.2 CONH.sub.2,                                                                          CH.sup.t CHCONH.sub.2,                                      CH.sub.2 CONH.sub.2,                                                                            CH.sub.2 SMe, and                                           SCF.sub.3,        CH.sup.c CHCN.                                              SO.sub.2 N(CH.sub.2 CH.sub.2 OH).sub.2,                                        ##STR69##                                                                     ##STR70##                                                                     ##STR71##                                                                    ______________________________________                                    


7. The compound of the formula: ##STR72## wherein R, R², M, and R^(a)are selected from the group consisting of:

    __________________________________________________________________________    #  R   R.sup.2   M  R.sup.a      R.sup.a position                             __________________________________________________________________________     1 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OCH.sub.3    5                                             2 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OCH.sub.2 CO.sub.2 Na                                                                      5                                             3 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OCH.sub.2 CH.sub.2 OH                                                                      5                                             4 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CF.sub.3     5                                             5 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         F            5                                             6 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          Cl           5                                             7 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          Br           5                                             8 H   CH.sub.2 OH                                                                             K.sup.+                                                                          I            5                                             9 β-CH.sub.3                                                                   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OH           5                                            10 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OCOCH.sub.3  5                                            11 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          OCONH.sub.2  5                                            12 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SCH.sub.3    5                                            13 H   (R)CH(F)CH.sub. 3                                                                       K.sup.+                                                                          SOCH.sub.3   5                                            14 β-CH.sub.3                                                                   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SO.sub.2 CH.sub.3                                                                          5                                            15 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SCH.sub.2 CH.sub.2 OH                                                                      5                                            16 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SOCH.sub.2 CH.sub.2 OH                                                                     5                                            17 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SO.sub.2 CH.sub.2 CH.sub.2 OH                                                              5                                            18 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SO.sub.2 NH.sub.2                                                                          5                                            19 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SO.sub.2 N(CH.sub.3).sub.2                                                                 5                                            20 H   CF.sub.2 CH.sub.3                                                                       K.sup.+                                                                          NHCHO        5                                            21 β-CH.sub.3                                                                   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          NHCOCH.sub.3 5                                            22 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          NHCO.sub.2 CH.sub.3                                                                        5                                            23 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          NHSO.sub.2 CH.sub.3                                                                        5                                            24 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CN           5                                            25 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHO          5                                            26 H   CH.sub.2 OH                                                                             K.sup.+                                                                          COCH.sub. 3  5                                            27 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          COCH.sub.2 OH                                                                              5                                            28 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHNOH        5                                            29 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHNOCH.sub.3 5                                            30 α-CH.sub.3                                                                  (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHNOCH.sub.2 CO.sub.2 H                                                                    5                                            31 α-CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                       K.sup.+                                                                          CHNOCMe.sub.2 CO.sub.2 H                                                                   5                                            32 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHNOCMe.sub.2 CO.sub.2 Me                                                                  5                                            33 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CO.sub.2 CH.sub.2 CH.sub.2 OH                                                              5                                            34 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONH.sub.2   5                                            35 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHCH.sub.3 5                                            36 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CON(CH.sub.3).sub.2                                                                        5                                            37 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHCH.sub.2 CN                                                                            5                                            38 β-CH.sub.3                                                                   CF.sub.2 CH.sub.3                                                                       K.sup.+                                                                          CONHCH.sub.2 CONH.sub.2                                                                    5                                            39 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHCH.sub. 2 CO.sub.2 H                                                                   5                                            40 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CONHOH       5                                            41 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHOCH.sub.3                                                                              5                                            42 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                      tetrazolyl                                                                       5                                                                          43 H   CH.sub.2 OH                                                                             K.sup.+                                                                          CO.sub.2 Na  5                                            44 H   (R)CH(OH)CF.sub.3                                                                       K.sup.+                                                                          SCF.sub.3    5                                            45 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          PO.sub.3 NaH 5                                            46 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHSO.sub.2 Ph                                                                            5                                            47 β-CH.sub.3                                                                   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CONHSO.sub.2 NH.sub.2                                                                      5                                            48 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SO.sub.3 Na  5                                            49 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          SO.sub.2 NHCN                                                                              5                                            50 β-CH.sub.3                                                                   (R)CH(F)CH.sub.3                                                                        K.sup.+                                                                          SO.sub.2 NHCONH.sub.2                                                                      5                                            51 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHCHCN       5                                            52 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHCHCONH.sub.2                                                                             5                                            53 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CHCHCO.sub.2 Na                                                                            5                                            54 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CCCONH.sub.2 5                                            55 β-CH.sub.3                                                                   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CCCN         5                                            56 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CH.sub.2 OH  4'                                           57 H   CH.sub.2 CH.sub.3                                                                       K.sup.+                                                                          CH.sub.2 N.sub.3                                                                           5                                            58 H   (R)CH(OH)CH.sub.3                                                                       K.sup.+                                                                          CH.sub.2 CO.sub.2 Na                                                                       5                                            59 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SOCH.sub.3   5                                            60 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SO.sub.2 CH.sub.3                                                                          5                                            61 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         NHCHO        5                                            62 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         NHCOMe       5                                            63 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         COCH.sub.3   5                                            64 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         COCF.sub.3   5                                            65 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         COCH.sub.2 CONH.sub.2                                                                      5                                            66 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CH.sub.2 CONH.sub.2                                                                        5                                            67 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CONHCH.sub.2 CONH.sub.2                                                                    5                                            68 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SCF.sub.3    5                                            69 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CONHSO.sub.2 NH.sub.2                                                                      5                                            70 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCH.sub.2 CH.sub.2 OH                                                                      4'                                           71 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCH.sub.2 CH.sub.2 OH                                                                      5'                                           72 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCOCH.sub.3  4'                                           73 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCOCH.sub.3  3'                                           74 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCONH.sub.2  4'                                           75 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SCH.sub.2 CH.sub.2 OH                                                                      5'                                           76 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SCH.sub.2 CH.sub.2 OH                                                                      4'                                           77 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SCH.sub.2 CH.sub.2 OH                                                                      3'                                           78 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CHO          4'                                           79 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CHO          3'                                           80 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CHO          5, 4'                                        81 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         COCH.sub.2 OH                                                                              4'                                           82 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SO.sub.2 N(CH.sub.2 CH.sub.2 OH).sub.2                                                     5                                            83 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          ##STR73##   5                                            84 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          ##STR74##   5                                            85 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                          ##STR75##   5                                            86 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CO.sub.2 Me  5                                            87 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         F            3'                                           88 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CH.sup.t CHCN                                                                              4'                                           89 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CH.sup.t CHCONH.sub.2                                                                      4'                                           90 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CN           4'                                           91 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OH           3'                                           92 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OH           4'                                           93 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CH.sub.2 SMe 4'                                           94 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OCONH.sub.2  3'                                           95 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SOMe         4'                                           96 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SO.sub.2 CH.sub.3                                                                          4'                                           97 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SMe          4'                                           98 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         CH.sup.c CHCN                                                                              4'                                           99 H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OH           3', 4'                                       100                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OH           3', 4', 5'                                   101                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         OH           5, 3', 4'                                    102                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         F            5, 4'                                        103                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         F            5, 3'                                        104                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SMe          5, 3',                                       and                                                                           105                                                                              H   (R)CH(OH)CH.sub.3                                                                       Na.sup.+                                                                         SMe          5, 4'.                                       __________________________________________________________________________


8. The compound of the formula: ##STR76## wherein R, R² and R^(a) areselected from the group consisting of:

    __________________________________________________________________________                   R.sup.a                                                        R   R.sup.2    5      5'   4'     3'                                          __________________________________________________________________________    --H (R)--CH(OH)CH.sub.3                                                                      --CHO  --H  --OH   --H                                         --H (R)--CH(OH)CH.sub.3                                                                      --CHO  --H  --F    --H                                         --H (R)--CH(OH)CH.sub.3                                                                      --CHO  --CHO                                                                              --F    --H                                         --H (R)--CH(OH)CH.sub.3                                                                      --SCH.sub.3                                                                          --H  --OH   --H                                         --H (R)--CH(OH)CH.sub.3                                                                      --SCH.sub.3                                                                          --H  --SOCH.sub.3                                                                         --H                                         --H (R)--CH(OH)CH.sub.3                                                                      --SCH.sub.3                                                                          --CHO                                                                              --H    --H                                         --H (R)--CH(OH)CH.sub.3                                                                      --SCH.sub.3                                                                          --H  --CH.sub.2 OH                                                                        --H                                         --H (R)--CH(OH)CH.sub.3                                                                      --CONH.sub.2                                                                         --H  --CHO  --H                                         --H (R)--CH(OH)CH.sub.3                                                                      --CONH.sub.2                                                                         --F  --CHO  --H                                         --H (R)--CH(F)CH.sub.3                                                                       --CONH.sub.2                                                                         --H  --CH.sub.2 OH                                                                        --H                                         β-CH3                                                                        (R)--CH(OH)CH3                                                                           --CONH.sub.2                                                                         --H  --SOCH.sub.3                                                                         --H                                         --H --CH.sub.2 OH                                                                            --SCH.sub.3                                                                          --H  --CHO  --H                                         -- H                                                                              (R)--CH(OH)CH.sub.3                                                                      --CN   --H  --SOCH.sub.3                                                                         --H                                         --H (R)--CH(OH)CH.sub.3                                                                      --CN   --H  --CONH.sub.2                                                                         --H                                         --H (R)--CH(OH)CH.sub.3                                                                      --CN   --H  --OH   --OH                                        --H (R)--CH(OH)CH.sub.3                                                                      --CN   --H  --CHO  --H                                         --H (R)--CH(OH)CH.sub.3                                                                      --SO.sub.2 CH.sub.3                                                                  --H  --CHO  --H,                                        and                                                                           --H (R)--CH(OH)CH.sub.3                                                                      --SO.sub.2 CH.sub.3                                                                  --H  --CONH.sub.2                                                                         --H.                                        __________________________________________________________________________


9. The compound of the formula: ##STR77## wherein R', R, R^(a), and Mare selected from the group consisting of:

    __________________________________________________________________________    R.sup.a                                                                       R  R  5         3'    4'        5' M                                          __________________________________________________________________________    OH H  H         H     H         H  K                                          OH H  F         H     H         H  K                                          OH H  OCH.sub.3 H     H         H  K                                          OH H  OH        H     H         H  Na                                         OH H  SCH.sub.3 H     H         H  Na                                         OH H  S(O)CH.sub.3                                                                            H     H         H  K                                          OH H  SO.sub.2 CH.sub.3                                                                       H     H         H  Na                                         OH H  CN        H     H         H  Na                                         OH H  CO.sub.2 Na                                                                             H     H         H  Na                                         OH H  CONH.sub.2                                                                              H     H         H  Na                                         OH H  CO.sub.2 CH.sub.3                                                                       H     H         H  Na                                         OH H  OCOCH.sub.3                                                                             H     H         H  Na                                         OH H  H         OH    H         H  Na                                         OH H  H         F     H         H  Na                                         OH H  CH.sub.2 OH                                                                             H     H         H  Na                                         OH H  CHO       H     H         H  Na                                         OH H  SCH.sub.2 CH.sub.2 OH                                                                   H     H         H  Na                                         OH H  SO.sub.2 CH.sub.2 CH.sub.2 OH                                                           H     H         H  Na                                         OH H  S(O)CH.sub.2 CH.sub.2 OH                                                                H     H         H  Na                                         OH H  SO.sub.2 NH.sub. 2                                                                      H     H         H  Na                                         OH H  SO.sub.2 NHCH.sub.3                                                                     H     H         H  Na                                         OH H  SO.sub.2 N(CH.sub.3).sub.2                                                              H     H         H  Na                                         OH H                                                                                 ##STR78##                                                                              H     H         H  Na                                         OH H  COCH.sub.3                                                                              H     H         H  Na                                         OH H  CONHCH.sub.3                                                                            H     H         H  Na                                         OH H  CON(CH.sub.3).sub.2                                                                     H     H         H  Na                                         OH H  Br        H     H         H  Na                                         OH H  SO.sub.2 CHCH.sub.2                                                                     H     H         H  Na                                         OH H  H         OCONH.sub.2                                                                         H         H  Na                                         OH H  H         H     OH        H  Na                                         OH H  H         H     CH.sub.2 OH                                                                             H  K                                          OH H  F         H     CH.sub.2 OH                                                                             H  Na                                         OH H  F         H     OCOCH.sub.3                                                                             H  Na                                         OH H  F         H     OH        H  Na                                         OH H  F         H     OCONH.sub.2                                                                             H  Na                                         OH H  H         H     CN        H  Na                                         OH H  H         H     CHCHCONH.sub.2                                                                          H  K                                                                (trans)                                                 OH H  H         H     CHCHCN    H  K                                                                (trans)                                                 OH H  H         H     SCH.sub.3 H  Na                                         OH H  H         H     SOCH.sub.3                                                                              H  Na                                         OH H  H         H     SO.sub.2 CH.sub.3                                                                       H  Na                                         F  H  H         H     CH.sub.2 OH                                                                             H  K                                          OH H  H         H     CH.sub.2 SCH.sub.3                                                                      H  K                                          OH βMe                                                                         H         H     CH.sub.2 OH                                                                             H  K                                          OH H  H         H     NMe-imidazole-                                                                          H  Na,                                                              2-thiomethyl                                            and                                                                           OH βMe                                                                         H         H     H         H  K.                                         __________________________________________________________________________


10. The compound of the formula: ##STR79## wherein R', R, R^(a) and Mare selected from the group consisting of:

    __________________________________________________________________________    R.sup.a                                                                       R' R  5          3'    4'       5' M                                          __________________________________________________________________________    F  βMe                                                                         CN         H     SOCH.sub.3                                                                             H  Na                                         F  H  OH         H     SOCH.sub.3                                                                             H  Na                                         OH βMe                                                                         F          H     SO.sub.2 NH.sub.2                                                                      H  Na                                         OH H  H          H     OH       OH Na                                         OH H  F          H     OH       OH Na                                         OH H  CONH.sub.2 OH    OH       H  Na                                         OH H  SO.sub.3 Na                                                                              H     H        H  Na                                         OH H  PO.sub.3 Na                                                                              H     H        H  Na                                         OH H  H          SO.sub.2 NH.sub.2                                                                   H        H  Na                                         OH H  CF.sub.3   H     H        H  Na                                         OH H  SCF.sub.3  H     H        H  Na                                         OH H  SCN        H     H        H  Na                                         OH H  SO.sub.2 CH.sub.2 CH.sub.2 CONH.sub.2                                                    H     H        H  Na                                         HO H  CONHCH.sub.2 CONH.sub.2                                                                  H     H        H  Na                                         HO H  COCF.sub.3 H     H        H  Na                                         HO H  COCH.sub.2 CONH.sub.2                                                                    H     H        H  Na                                         HO H  OCH.sub.2 CH.sub.2 OH                                                                    H     H        H  Na                                         HO H  H          H     OCH.sub.2 CH.sub.2 OH                                                                  H  Na                                         HO H  H          H     SCH.sub.2 CH.sub.2 OH                                                                  H  Na                                         HO H  H          H     SO.sub.2 CH.sub.2 CH2OH                                                                H  Na                                         HO H  H          H     S(O)CH.sub.2 CH.sub.2 OH                                                               H  Na                                         HO H  CH.sub.2 CONH.sub.2                                                                      H     H        H  Na                                         HO H  SCH.sub.2 CONH.sub.2                                                                     H     H        H  Na                                         HO H  SCH.sub.2 CN                                                                             H     H        H  Na                                         HO H  PO.sub.2 NH.sub.2                                                                        H     H        H  Na                                         HO H  SCH.sub.2 CH.sub.2 CN                                                                    H     H        H  Na,                                        and                                                                           HO H  SCH.sub.2 CH.sub.2 F                                                                     H     H        H  Na.                                        __________________________________________________________________________


11. A pharmaceutical composition effective against bacteria comprisingan effective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier therefor.
 12. A method for treating bacterialinfection in mammals comprising administering a pharmaceuticalcomposition an comprising an effective amount of a compound of claim 1and a pharmaceutically acceptable carrier therefor.
 13. A compositionaccording to claim 11 which further comprises an inhibitorily effectiveamount of a DHP inhibitor.
 14. A composition according to claim 13wherein said DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptanoicacid.
 15. A method according to claim 12 which further comprisesadministering an inhibitorily effective amount of a DHP inhibitor.
 16. Amethod according to claim 15 wherein said DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptanoicacid.